Abstract
The efficient study of human disease requires the proper tools, one of the most crucial of which is an accurate animal model that faithfully recapitulates the human condition. The study of amyotrophic lateral sclerosis (ALS) is no exception. Although the majority of ALS cases are considered sporadic, most animal models of this disease rely on genetic mutations identified in familial cases. Over the past decade, the number of genes associated with ALS has risen dramatically and, with each new genetic variant, there is a drive to develop associated animal models. Rodent models are of particular importance as they allow for the study of ALS in the context of a living mammal with a comparable CNS. Such models not only help to verify the pathogenicity of novel mutations but also provide critical insight into disease mechanisms and are crucial for the testing of new therapeutics. In this Review, we aim to summarize the full spectrum of ALS rodent models developed to date.
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References
Cook, C. & Petrucelli, L. Genetic convergence brings clarity to the enigmatic red line in ALS. Neuron 101, 1057–1069 (2019).
Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).
Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994). This report documents the first genetic mouse model of ALS: a transgenic model of SOD1-G93A that remains popular to date.
Gurney, M. E., Fleck, T. J., Himes, C. S. & Hall, E. D. Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis. Neurology 50, 62–66 (1998).
Ito, H. et al. Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp. Neurol. 213, 448–455 (2008).
Wong, P. C. et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14, 1105–1116 (1995).
Bruijn, L. I. et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18, 327–338 (1997).
Ripps, M. E., Huntley, G. W., Hof, P. R., Morrison, J. H. & Gordon, J. W. Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 92, 689–693 (1995).
Jonsson, P. A. et al. Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1. J. Neuropathol. Exp. Neurol. 65, 1126–1136 (2006).
Chang-Hong, R. et al. Neuroprotective effect of oxidized galectin-1 in a transgenic mouse model of amyotrophic lateral sclerosis. Exp. Neurol. 194, 203–211 (2005).
Joyce, P. I. et al. A novel SOD1-ALS mutation separates central and peripheral effects of mutant SOD1 toxicity. Hum. Mol. Genet. 24, 1883–1897 (2015).
Muller, F. L. et al. Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy. Free Radic. Biol. Med. 40, 1993–2004 (2006).
Fischer, L. R., Li, Y., Asress, S. A., Jones, D. P. & Glass, J. D. Absence of SOD1 leads to oxidative stress in peripheral nerve and causes a progressive distal motor axonopathy. Exp. Neurol. 233, 163–171 (2012).
Philips, T. & Rothstein, J. D. Rodent models of amyotrophic lateral sclerosis. Curr. Protoc. Pharmacol. 69, 5.67.1–5.67.21 (2015).
Trist, B. G., Hilton, J. B., Hare, D. J., Crouch, P. J. & Double, K. L. Superoxide dismutase 1 in health and disease: how a frontline antioxidant becomes neurotoxic. Angew. Chem. Int. Ed. 60, 9215–9246 (2021).
Kato, S., Saito, M., Hirano, A. & Ohama, E. Recent advances in research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations: neuronal Lewy body-like hyaline inclusions and astrocytic hyaline inclusions. Histol. Histopathol. 14, 973–989 (1999).
Shibata, N., Asayama, K., Hirano, A. & Kobayashi, M. Immunohistochemical study on superoxide dismutases in spinal cords from autopsied patients with amyotrophic lateral sclerosis. Dev. Neurosci. 18, 492–498 (1996).
Wicks, P. et al. SOD1 and cognitive dysfunction in familial amyotrophic lateral sclerosis. J. Neurol. 256, 234–241 (2009).
Katz, J. S., Katzberg, H. D., Woolley, S. C., Marklund, S. L. & Andersen, P. M. Combined fulminant frontotemporal dementia and amyotrophic lateral sclerosis associated with an I113T SOD1 mutation. Amyotroph. Lateral Scler. 13, 567–569 (2012).
Martinelli, I. et al. A novel p.N66T mutation in exon 3 of the SOD1 gene: report of two families of ALS patients with early cognitive impairment. Amyotroph. Lateral Scler. Frontotemporal Degener. 21, 296–300 (2020).
Nakamura, M. et al. A truncating SOD1 mutation, p.Gly141X, is associated with clinical and pathologic heterogeneity, including frontotemporal lobar degeneration. Acta Neuropathol. 130, 145–157 (2015).
Rothstein, J. D. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann. Neurol. 65 (Suppl. 1), S3–S9 (2009).
Geser, F., Martinez-Lage, M., Kwong, L. K., Lee, V. M. & Trojanowski, J. Q. Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J. Neurol. 256, 1205–1214 (2009).
Da Cruz, S. et al. Misfolded SOD1 is not a primary component of sporadic ALS. Acta Neuropathol. 134, 97–111 (2017).
Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
Mackenzie, I. R. et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann. Neurol. 61, 427–434 (2007).
Arai, T. et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602–611 (2006).
Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208–1211 (2009).
Deng, H. X. et al. FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann. Neurol. 67, 739–748 (2010).
Tyzack, G. E. et al. Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis. Brain 142, 2572–2580 (2019).
Ikenaka, K. et al. Characteristic Features of FUS inclusions in spinal motor neurons of sporadic amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 79, 370–377 (2020).
Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).
Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572–574 (2008).
Rutherford, N. J. et al. Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet. 4, e1000193 (2008).
Kwiatkowski, T. J. Jr. et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205–1208 (2009).
Couthouis, J. et al. A yeast functional screen predicts new candidate ALS disease genes. Proc. Natl Acad. Sci. USA 108, 20881–20890 (2011).
Conicella, A. E., Zerze, G. H., Mittal, J. & Fawzi, N. L. ALS mutations disrupt phase separation mediated by alpha-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24, 1537–1549 (2016).
Kwon, I. et al. Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 155, 1049–1060 (2013).
Kwon, I. et al. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345, 1139–1145 (2014).
Han, T. W. et al. Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. Cell 149, 768–779 (2012).
Kato, M. et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753–767 (2012).
Davidson, Y. et al. Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol. 113, 521–533 (2007).
Neumann, M. et al. Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol. 117, 137–149 (2009).
Wils, H. et al. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc. Natl Acad. Sci. USA 107, 3858–3863 (2010).
Stallings, N. R., Puttaparthi, K., Luther, C. M., Burns, D. K. & Elliott, J. L. Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol. Dis. 40, 404–414 (2010).
Xu, Y. F. et al. Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J. Neurosci. 30, 10851–10859 (2010).
Tsuiji, H. et al. TDP-43 accelerates age-dependent degeneration of interneurons. Sci. Rep. 7, 14972 (2017).
Wang, D. B. et al. Expansive gene transfer in the rat CNS rapidly produces amyotrophic lateral sclerosis relevant sequelae when TDP-43 is overexpressed. Mol. Ther. 18, 2064–2074 (2010).
Jackson, K. L., Dayton, R. D., Deverman, B. E. & Klein, R. L. Better targeting, better efficiency for wide-scale neuronal transduction with the synapsin promoter and AAV-PHP.B. Front. Mol. Neurosci. 9, 116 (2016).
Igaz, L. M. et al. Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J. Clin. Invest. 121, 726–738 (2011).
Sasaguri, H. et al. The extreme N-terminus of TDP-43 mediates the cytoplasmic aggregation of TDP-43 and associated toxicity in vivo. Brain Res. 1647, 57–64 (2016).
Walker, A. K. et al. Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43. Acta Neuropathol. 130, 643–660 (2015). Unfortunately, most TDP43 mouse models fail to recapitulate the expected cytoplasmic inclusions; the authors of this report, and a previous study, overcame this hurdle by engineering mice to express TDP43 with a mutant nuclear localization sequence.
Nishino, K. et al. Mice deficient in the C-terminal domain of TAR DNA-binding protein 43 develop age-dependent motor dysfunction associated with impaired Notch1-Akt signaling pathway. Acta Neuropathol. Commun. 7, 118 (2019).
Sugai, A. et al. Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation. Neurobiol. Dis. 130, 104534 (2019).
Kraemer, B. C. et al. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol. 119, 409–419 (2010).
Wu, L. S., Cheng, W. C. & Shen, C. K. Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. J. Biol. Chem. 287, 27335–27344 (2012).
Wu, L. S. et al. Transcriptomopathies of pre- and post-symptomatic frontotemporal dementia-like mice with TDP-43 depletion in forebrain neurons. Acta Neuropathol. Commun. 7, 50 (2019).
Yang, C. et al. Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 111, E1121–E1129 (2014).
Paolicelli, R. C. et al. TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron 95, 297–308.e6 (2017).
Koza, P. et al. Neuronal TDP-43 depletion affects activity-dependent plasticity. Neurobiol. Dis. 130, 104499 (2019).
Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M. & Baloh, R. H. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc. Natl Acad. Sci. USA 106, 18809–18814 (2009).
Guo, Y. et al. HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice. Brain Res. 1460, 88–95 (2012).
Esmaeili, M. A., Panahi, M., Yadav, S., Hennings, L. & Kiaei, M. Premature death of TDP-43 (A315T) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis. Int. J. Exp. Pathol. 94, 56–64 (2013).
Hatzipetros, T. et al. C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS. Brain Res. 1584, 59–72 (2014).
Herdewyn, S. et al. Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP-43 (A315T) mice. Mol. Neurodegener. 9, 24 (2014).
Chen, S. et al. Riluzole exhibits no therapeutic efficacy on a transgenic rat model of amyotrophic lateral sclerosis. Curr. Neurovasc Res. 17, 275–285 (2020).
Gordon, D. et al. Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction. Neurobiol. Dis. 121, 148–162 (2019).
Huang, S. L. et al. A robust TDP-43 knock-in mouse model of ALS. Acta Neuropathol. Commun. 8, 3 (2020). While most knock-in models of Tdp43 only show ALS-like phenotypes at advanced ages, this model saw phenotypes as early as 6 months of age.
Watanabe, S. et al. ALS-linked TDP-43(M337V) knock-in mice exhibit splicing deregulation without neurodegeneration. Mol. Brain 13, 8 (2020).
Ebstein, S. Y., Yagudayeva, I. & Shneider, N. A. Mutant TDP-43 causes early-stage dose-dependent motor neuron degeneration in a TARDBP knockin mouse model of ALS. Cell Rep. 26, 364–373.e4 (2019).
Muller, H. P. et al. Longitudinal diffusion tensor magnetic resonance imaging analysis at the cohort level reveals disturbed cortical and callosal microstructure with spared corticospinal tract in the TDP-43 (G298S) ALS mouse model. Transl. Neurodegener. 8, 27 (2019).
White, M. A. et al. TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD. Nat. Neurosci. 21, 552–563 (2018).
Fratta, P. et al. Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis. EMBO J. 37, e98684 (2018).
Birsa, N., Bentham, M. P. & Fratta, P. Cytoplasmic functions of TDP-43 and FUS and their role in ALS. Semin. Cell Dev. Biol. 99, 193–201 (2020).
Ishigaki, S. & Sobue, G. Importance of Functional Loss of FUS in FTLD/ALS. Front. Mol. Biosci. 5, 44 (2018).
Chen, C., Ding, X., Akram, N., Xue, S. & Luo, S. Z. Fused in sarcoma: properties, self-assembly and correlation with neurodegenerative diseases. Molecules 24, 1622 (2019).
Dormann, D. et al. ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import. EMBO J. 29, 2841–2857 (2010).
Patel, A. et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066–1077 (2015).
Murakami, T. et al. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron 88, 678–690 (2015).
Ratti, A. & Buratti, E. Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J. Neurochem. 138, 95–111 (2016).
Olszewska, D. A., Lonergan, R., Fallon, E. M. & Lynch, T. Genetics of frontotemporal dementia. Curr. Neurol. Neurosci. Rep. 16, 107 (2016).
Mackenzie, I. R. et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 119, 1–4 (2010).
Snowden, J. S. et al. The most common type of FTLD-FUS (aFTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene. Acta Neuropathol. 122, 99–110 (2011).
Sabatelli, M. et al. Mutations in the 3’ untranslated region of FUS causing FUS overexpression are associated with amyotrophic lateral sclerosis. Hum. Mol. Genet. 22, 4748–4755 (2013).
Dini Modigliani, S., Morlando, M., Errichelli, L., Sabatelli, M. & Bozzoni, I. An ALS-associated mutation in the FUS 3’-UTR disrupts a microRNA-FUS regulatory circuitry. Nat. Commun. 5, 4335 (2014).
Mitchell, J. C. et al. Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol. 125, 273–288 (2013).
Ling, S. C. et al. Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis. eLife 8, e40811 (2019).
Huang, C. et al. FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet. 7, e1002011 (2011). Using rats as a model system, this group documents the first rodent model to express an ALS-associated FUS mutation, FUS-R521C.
Kuroda, M. et al. Male sterility and enhanced radiation sensitivity in TLS(-/-) mice. EMBO J. 19, 453–462 (2000).
Hicks, G. G. et al. Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat. Genet. 24, 175–179 (2000).
Scekic-Zahirovic, J. et al. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss. EMBO J. 35, 1077–1097 (2016).
Kino, Y. et al. FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 3, 24 (2015).
Yokoi, S. et al. 3’UTR length-dependent control of SynGAP isoform alpha2 mRNA by FUS and ELAV-like proteins promotes dendritic spine maturation and cognitive function. Cell Rep. 20, 3071–3084 (2017).
Udagawa, T. et al. FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization. Nat. Commun. 6, 7098 (2015).
Ishigaki, S. et al. Altered Tau isoform ratio caused by loss of FUS and SFPQ function leads to FTLD-like phenotypes. Cell Rep. 18, 1118–1131 (2017).
Sharma, A. et al. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat. Commun. 7, 10465 (2016).
Qiu, H. et al. ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. J. Clin. Invest. 124, 981–999 (2014).
Lopez-Erauskin, J. et al. ALS/FTD-linked mutation in FUS suppresses intra-axonal protein synthesis and drives disease without nuclear loss-of-function of FUS. Neuron 100, 816–830.e7 (2018).
Zhang, X. et al. In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model. Brain 143, 1350–1367 (2020).
Sephton, C. F. et al. Activity-dependent FUS dysregulation disrupts synaptic homeostasis. Proc. Natl Acad. Sci. USA 111, E4769–E4778 (2014).
Shiihashi, G. et al. Dendritic homeostasis disruption in a novel frontotemporal dementia mouse model expressing cytoplasmic fused in sarcoma. EBioMedicine 24, 102–115 (2017).
Shiihashi, G. et al. Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice. Brain 139, 2380–2394 (2016).
Picchiarelli, G. et al. FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis. Nat. Neurosci. 22, 1793–1805 (2019).
Scekic-Zahirovic, J. et al. Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis. Acta Neuropathol. 133, 887–906 (2017).
Verbeeck, C. et al. Expression of fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis. Mol. Neurodegener. 7, 53 (2012).
Devoy, A. et al. Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in ‘FUSDelta14’ knockin mice. Brain 140, 2797–2805 (2017).
DeJesus-Hernandez, M. et al. De novo truncating FUS gene mutation as a cause of sporadic amyotrophic lateral sclerosis. Hum. Mutat. 31, E1377–E1389 (2010).
Chesi, A. et al. Exome sequencing to identify de novo mutations in sporadic ALS trios. Nat. Neurosci. 16, 851–855 (2013).
Staahl, B. T. et al. Kinetic analysis of npBAF to nBAF switching reveals exchange of SS18 with CREST and integration with neural developmental pathways. J. Neurosci. 33, 10348–10361 (2013).
Park, S. et al. Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies. PLoS Genet. 15, e1008308 (2019).
Kukharsky, M. S. et al. Calcium-responsive transactivator (CREST) protein shares a set of structural and functional traits with other proteins associated with amyotrophic lateral sclerosis. Mol. Neurodegener. 10, 20 (2015).
Cheng, C. et al. Loss of CREST leads to neuroinflammatory responses and ALS-like motor defects in mice. Transl. Neurodegener. 8, 13 (2019). The authors developed the main mouse models of CREST-related ALS by generating both a mutant transgenic model and a knockout; their study argues that this disease arises from a loss of CREST function.
Aizawa, H. et al. Dendrite development regulated by CREST, a calcium-regulated transcriptional activator. Science 303, 197–202 (2004).
Johnson, J. O. et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat. Neurosci. 17, 664–666 (2014).
Coelho, M. B. et al. Nuclear matrix protein Matrin3 regulates alternative splicing and forms overlapping regulatory networks with PTB. EMBO J. 34, 653–668 (2015).
Banerjee, A., Vest, K. E., Pavlath, G. K. & Corbett, A. H. Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing. Nucleic Acids Res. 45, 10706–10725 (2017).
Gallego-Iradi, M. C. et al. N-terminal sequences in matrin 3 mediate phase separation into droplet-like structures that recruit TDP43 variants lacking RNA binding elements. Lab. Invest. 99, 1030–1040 (2019).
Tada, M. et al. Matrin 3 is a component of neuronal cytoplasmic inclusions of motor neurons in sporadic amyotrophic lateral sclerosis. Am. J. Pathol. 188, 507–514 (2018).
Quintero-Rivera, F. et al. MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus. Hum. Mol. Genet. 24, 2375–2389 (2015).
Moloney, C. et al. Analysis of spinal and muscle pathology in transgenic mice overexpressing wild-type and ALS-linked mutant MATR3. Acta Neuropathol. Commun. 6, 137 (2018).
Zhang, X. et al. A mutant MATR3 mouse model to explain multisystem proteinopathy. J. Pathol. 249, 182–192 (2019).
Barp, A. et al. The first French case of MATR3-related distal myopathy: clinical, radiological and histopathological characterization. Rev. Neurol. 174, 752–755 (2018).
Feit, H. et al. Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31. Am. J. Hum. Genet. 63, 1732–1742 (1998).
Muller, T. J. et al. Phenotype of matrin-3-related distal myopathy in 16 German patients. Ann. Neurol. 76, 669–680 (2014).
Palmio, J. et al. Re-evaluation of the phenotype caused by the common MATR3 p.Ser85Cys mutation in a new family. J. Neurol. Neurosurg. Psychiatry 87, 448–450 (2016).
Yamashita, S. et al. Clinicopathological features of the first Asian family having vocal cord and pharyngeal weakness with distal myopathy due to a MATR3 mutation. Neuropathol. Appl. Neurobiol. 41, 391–398 (2015).
Senderek, J. et al. Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3. Am. J. Hum. Genet. 84, 511–518 (2009).
Kao, C. S. et al. Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS. Nat. Commun. 11, 5304 (2020). While previous models of mutant MATR3 showed more myopathic changes, this recent knock-in model shows phenotypes more akin to ALS.
Chance, P. F. et al. Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am. J. Hum. Genet. 62, 633–640 (1998).
Chen, Y. Z. et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am. J. Hum. Genet. 74, 1128–1135 (2004).
Bennett, C. L. & La Spada, A. R. Senataxin, a novel helicase at the interface of RNA transcriptome regulation and neurobiology: from normal function to pathological roles in motor neuron disease and cerebellar degeneration. Adv. Neurobiol. 20, 265–281 (2018).
Bennett, C. L. et al. Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients. Acta Neuropathol. 136, 425–443 (2018). This report describes the first mouse models of ALS4: a transgenic model of SETX-R2136H and a knock-in model of SETX-L389S1.
Moreira, M. C. & Koenig, M. Ataxia with Oculomotor Apraxia Type 2 (eds Adam, M. P. et al.) (GeneReviews, 2004).
Narain, P. et al. Identification and characterization of novel and rare susceptible variants in Indian amyotrophic lateral sclerosis patients. Neurogenetics 20, 197–208 (2019).
Rabin, B. A. et al. Autosomal dominant juvenile amyotrophic lateral sclerosis. Brain 122, 1539–1550 (1999).
Halawani, D. & Latterich, M. p97: the cell’s molecular purgatory? Mol. Cell 22, 713–717 (2006).
Yamanaka, K., Sasagawa, Y. & Ogura, T. Recent advances in p97/VCP/Cdc48 cellular functions. Biochim. Biophys. Acta 1823, 130–137 (2012).
Watts, G. D. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 36, 377–381 (2004).
Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857–864 (2010).
DeJesus-Hernandez, M. et al. Novel p.Ile151Val mutation in VCP in a patient of African American descent with sporadic ALS. Neurology 77, 1102–1103 (2011).
Koppers, M. et al. VCP mutations in familial and sporadic amyotrophic lateral sclerosis. Neurobiol. Aging 33, 837.e7–837.e13 (2012).
Tiloca, C. et al. Mutational analysis of VCP gene in familial amyotrophic lateral sclerosis. Neurobiol. Aging 33, 630.e1–630.e2 (2012).
Abramzon, Y. et al. Valosin-containing protein (VCP) mutations in sporadic amyotrophic lateral sclerosis. Neurobiol. Aging 33, 2231.e1–2231.e6 (2012).
Hirano, M. et al. VCP gene analyses in Japanese patients with sporadic amyotrophic lateral sclerosis identify a new mutation. Neurobiol. Aging 36, 1604.e1–1604.e6 (2015).
Badadani, M. et al. VCP associated inclusion body myopathy and paget disease of bone knock-in mouse model exhibits tissue pathology typical of human disease. PLoS ONE5, e13183 (2010).
Nalbandian, A. et al. A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse. Muscle Nerve 47, 260–270 (2013).
Yin, H. Z. et al. Slow development of ALS-like spinal cord pathology in mutant valosin-containing protein gene knock-in mice. Cell Death Dis. 3, e374 (2012). Mouse models of VCP have primarily been studied in relation to IBMPFD; this report reveals that these mouse models also show ALS-like pathology with age.
Nalbandian, A. et al. The homozygote VCP(R155H/R155H) mouse model exhibits accelerated human VCP-associated disease pathology. PLoS ONE 7, e46308 (2012).
Deng, H. X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211–215 (2011).
Ko, H. S., Uehara, T., Tsuruma, K. & Nomura, Y. Ubiquilin interacts with ubiquitylated proteins and proteasome through its ubiquitin-associated and ubiquitin-like domains. FEBS Lett. 566, 110–114 (2004).
Hjerpe, R. et al. UBQLN2 mediates autophagy-independent protein aggregate clearance by the proteasome. Cell 166, 935–949 (2016).
Gorrie, G. H. et al. Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2. Proc. Natl Acad. Sci. USA 111, 14524–14529 (2014).
Radzicki, D., Liu, E., Deng, H. X., Siddique, T. & Martina, M. Early impairment of synaptic and intrinsic excitability in mice expressing ALS/dementia-linked mutant UBQLN2. Front. Cell Neurosci. 10, 216 (2016).
Ceballos-Diaz, C. et al. Viral expression of ALS-linked ubiquilin-2 mutants causes inclusion pathology and behavioral deficits in mice. Mol. Neurodegener. 10, 25 (2015).
Le, N. T. et al. Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations. Proc. Natl Acad. Sci. USA 113, E7580–E7589 (2016).
Wu, Q. et al. Pathogenic Ubqln2 gains toxic properties to induce neuron death. Acta Neuropathol. 129, 417–428 (2015).
Huang, B., Wu, Q., Zhou, H., Huang, C. & Xia, X. G. Increased Ubqln2 expression causes neuron death in transgenic rats. J. Neurochem. 139, 285–293 (2016).
Chen, T., Huang, B., Shi, X., Gao, L. & Huang, C. Mutant UBQLN2(P497H) in motor neurons leads to ALS-like phenotypes and defective autophagy in rats. Acta Neuropathol. Commun. 6, 122 (2018). Using a conditional rat model of UBQLN2-P497H, the authors of this study found that the motor neuron degeneration they observe is cell-autonomous.
Toth, R. P. & Atkin, J. D. Dysfunction of optineurin in amyotrophic lateral sclerosis and glaucoma. Front. Immunol. 9, 1017 (2018).
Maruyama, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465, 223–226 (2010).
Markovinovic, A. et al. Optineurin in amyotrophic lateral sclerosis: multifunctional adaptor protein at the crossroads of different neuroprotective mechanisms. Prog. Neurobiol. 154, 1–20 (2017).
Minegishi, Y., Nakayama, M., Iejima, D., Kawase, K. & Iwata, T. Significance of optineurin mutations in glaucoma and other diseases. Prog. Retin. Eye Res. 55, 149–181 (2016).
Pottier, C. et al. Identification of compound heterozygous variants in OPTN in an ALS-FTD patient from the CReATe consortium: a case report. Amyotroph. Lateral Scler. Frontotemporal Degener. 19, 469–471 (2018).
Tumer, Z. et al. Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS. Neurobiol. Aging 33, 208.e1–208.e5 (2012).
Weishaupt, J. H. et al. A novel optineurin truncating mutation and three glaucoma-associated missense variants in patients with familial amyotrophic lateral sclerosis in Germany. Neurobiol. Aging 34, 1516.e9–1516.e15 (2013).
Goldstein, O. et al. OPTN 691_692insAG is a founder mutation causing recessive ALS and increased risk in heterozygotes. Neurology 86, 446–453 (2016).
Cirulli, E. T. et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347, 1436–1441 (2015).
Liu, Z. et al. ALS-associated E478G mutation in human OPTN (Optineurin) promotes inflammation and induces neuronal cell death. Front. Immunol. 9, 2647 (2018).
Ito, Y. et al. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science 353, 603–608 (2016).
Korac, J. et al. Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates. J. Cell Sci. 126, 580–592 (2013).
Paulus, J. D. & Link, B. A. Loss of optineurin in vivo results in elevated cell death and alters axonal trafficking dynamics. PLoS ONE 9, e109922 (2014).
Gleason, C. E., Ordureau, A., Gourlay, R., Arthur, J. S. C. & Cohen, P. Polyubiquitin binding to optineurin is required for optimal activation of TANK-binding kinase 1 and production of interferon beta. J. Biol. Chem. 286, 35663–35674 (2011).
Munitic, I. et al. Optineurin insufficiency impairs IRF3 but not NF-kappaB activation in immune cells. J. Immunol. 191, 6231–6240 (2013).
Kurashige, T. et al. Optineurin defects cause TDP43-pathology with autophagic vacuolar formation. Neurobiol. Dis. 148, 105215 (2021). This recent Optn-knockout model showed TDP43 proteinopathy, supporting the hypothesis that ALS pathology could arise from a loss of optineurin function.
Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).
Ahmad, L., Zhang, S. Y., Casanova, J. L. & Sancho-Shimizu, V. Human TBK1: a gatekeeper of neuroinflammation. Trends Mol. Med. 22, 511–527 (2016).
Tsai, P. C. et al. Mutational analysis of TBK1 in Taiwanese patients with amyotrophic lateral sclerosis. Neurobiol. Aging 40, 191.e11–191.e16 (2016).
Pozzi, L. et al. TBK1 mutations in Italian patients with amyotrophic lateral sclerosis: genetic and functional characterisation. J. Neurol. Neurosurg. Psychiatry 88, 869–875 (2017).
Li, F. et al. Structural insights into the interaction and disease mechanism of neurodegenerative disease-associated optineurin and TBK1 proteins. Nat. Commun. 7, 12708 (2016).
Ye, J. et al. Effects of ALS-associated TANK binding kinase 1 mutations on protein-protein interactions and kinase activity. Proc. Natl Acad. Sci. USA 116, 24517–24526 (2019).
de Majo, M. et al. ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. Neurobiol. Aging 71, 266.e1–266.e10 (2018).
Minegishi, Y. et al. Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma. Hum. Mol. Genet. 22, 3559–3567 (2013).
Bonnard, M. et al. Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription. EMBO J. 19, 4976–4985 (2000).
Brenner, D. et al. Heterozygous Tbk1 loss has opposing effects in early and late stages of ALS in mice. J. Exp. Med. 216, 267–278 (2019).
Xu, D. et al. TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging. Cell 174, 1477–1491.e19 (2018).
Bruno, C. et al. Haploinsufficiency of TANK-binding kinase 1 prepones age-associated neuroinflammatory changes without causing motor neuron degeneration in aged mice. Brain Commun. 2, fcaa133 (2020).
Duan, W. et al. Deletion of Tbk1 disrupts autophagy and reproduces behavioral and locomotor symptoms of FTD-ALS in mice. Aging 11, 2457–2476 (2019).
Gerbino, V. et al. The loss of TBK1 kinase activity in motor neurons or in all cell types differentially impacts ALS disease progression in SOD1 mice. Neuron 106, 789–805.e5 (2020). This interesting study not only introduced the first mouse models to express ALS-associated mutations in TBK1 but also found that loss of TBK1 activity can have differential effects on ALS progression due to its varying roles in different cell types.
Cui, R., Tuo, M., Li, P. & Zhou, C. Association between TBK1 mutations and risk of amyotrophic lateral sclerosis/frontotemporal dementia spectrum: a meta-analysis. Neurol. Sci. 39, 811–820 (2018).
Pottier, C. et al. Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta Neuropathol. 130, 77–92 (2015).
Lattante, S. et al. Coexistence of variants in TBK1 and in other ALS-related genes elucidates an oligogenic model of pathogenesis in sporadic ALS. Neurobiol. Aging 84, 239.e9–239.e14 (2019).
Sieverding, K. et al. Hemizygous deletion of Tbk1 worsens neuromuscular junction pathology in TDP-43(G298S) transgenic mice. Exp. Neurol. 335, 113496 (2021).
Geng, J. et al. Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Nat. Commun. 8, 359 (2017).
Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440–1446 (2011).
Yilmaz, R. et al. SQSTM1/p62 variants in 486 patients with familial ALS from Germany and Sweden. Neurobiol. Aging 87, 139.e9–139.e15 (2020).
Rubino, E. et al. SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 79, 1556–1562 (2012).
Hirano, M. et al. Mutations in the gene encoding p62 in Japanese patients with amyotrophic lateral sclerosis. Neurology 80, 458–463 (2013).
Chen, Y. et al. SQSTM1 mutations in Han Chinese populations with sporadic amyotrophic lateral sclerosis. Neurobiol. Aging 35, 726.e7–726.e9 (2014).
Yang, Y. et al. Six SQSTM1 mutations in a Chinese amyotrophic lateral sclerosis cohort. Amyotroph. Lateral Scler. Frontotemporal Degener. 16, 378–384 (2015).
Sun, L. et al. Identification of a novel hemizygous SQSTM1 nonsense mutation in atypical behavioral variant frontotemporal dementia. Front. Aging Neurosci. 10, 26 (2018).
Dols-Icardo, O. et al. Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation. J. Neurol. Neurosurg. Psychiatry 89, 162–168 (2018).
Borghero, G. et al. TBK1 is associated with ALS and ALS-FTD in Sardinian patients. Neurobiol. Aging 43, 180.e1–180.e5 (2016).
Mizuno, Y. et al. Immunoreactivities of p62, an ubiqutin-binding protein, in the spinal anterior horn cells of patients with amyotrophic lateral sclerosis. J. Neurol. Sci. 249, 13–18 (2006).
King, A., Maekawa, S., Bodi, I., Troakes, C. & Al-Sarraj, S. Ubiquitinated, p62 immunopositive cerebellar cortical neuronal inclusions are evident across the spectrum of TDP-43 proteinopathies but are only rarely additionally immunopositive for phosphorylation-dependent TDP-43. Neuropathology 31, 239–249 (2011).
Rea, S. L., Majcher, V., Searle, M. S. & Layfield, R. SQSTM1 mutations — bridging Paget disease of bone and ALS/FTLD. Exp. Cell Res. 325, 27–37 (2014).
Teyssou, E. et al. Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. Acta Neuropathol. 125, 511–522 (2013).
Kwok, C. T., Morris, A. & de Belleroche, J. S. Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB. Eur. J. Hum. Genet. 22, 492–496 (2014).
Le Ber, I. et al. SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis. JAMA Neurol. 70, 1403–1410 (2013).
Daroszewska, A. et al. A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget’s disease-like disorder in mice. Hum. Mol. Genet. 20, 2734–2744 (2011).
Ramesh Babu, J. et al. Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. J. Neurochem. 106, 107–120 (2008).
Nishimura, A. L. et al. A novel locus for late onset amyotrophic lateral sclerosis/motor neurone disease variant at 20q13. J. Med. Genet. 41, 315–320 (2004).
Nishimura, A. L. et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet. 75, 822–831 (2004).
Kamemura, K. & Chihara, T. Multiple functions of the ER-resident VAP and its extracellular role in neural development and disease. J. Biochem. 165, 391–400 (2019).
Shi, J., Lua, S., Tong, J. S. & Song, J. Elimination of the native structure and solubility of the hVAPB MSP domain by the Pro56Ser mutation that causes amyotrophic lateral sclerosis. Biochemistry 49, 3887–3897 (2010).
Nakamichi, S., Yamanaka, K., Suzuki, M., Watanabe, T. & Kagiwada, S. Human VAPA and the yeast VAP Scs2p with an altered proline distribution can phenocopy amyotrophic lateral sclerosis-associated VAPB(P56S). Biochem. Biophys. Res. Commun. 404, 605–609 (2011).
Kim, S., Leal, S. S., Ben Halevy, D., Gomes, C. M. & Lev, S. Structural requirements for VAP-B oligomerization and their implication in amyotrophic lateral sclerosis-associated VAP-B(P56S) neurotoxicity. J. Biol. Chem. 285, 13839–13849 (2010).
Papiani, G. et al. Restructured endoplasmic reticulum generated by mutant amyotrophic lateral sclerosis-linked VAPB is cleared by the proteasome. J. Cell Sci. 125, 3601–3611 (2012).
Fasana, E. et al. A VAPB mutant linked to amyotrophic lateral sclerosis generates a novel form of organized smooth endoplasmic reticulum. FASEB J. 24, 1419–1430 (2010).
Tudor, E. L. et al. Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology. Neuroscience 167, 774–785 (2010).
Qiu, L. et al. Widespread aggregation of mutant VAPB associated with ALS does not cause motor neuron degeneration or modulate mutant SOD1 aggregation and toxicity in mice. Mol. Neurodegener. 8, 1 (2013).
Kuijpers, M. et al. Amyotrophic lateral sclerosis (ALS)-associated VAPB-P56S inclusions represent an ER quality control compartment. Acta Neuropathol. Commun. 1, 24 (2013).
Aliaga, L. et al. Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons. Hum. Mol. Genet. 22, 4293–4305 (2013).
Cadoni, M. P. L. et al. VAPB ER-aggregates, a possible new biomarker in ALS pathology. Cells 9, 164 (2020).
Mitne-Neto, M. et al. Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. Hum. Mol. Genet. 20, 3642–3652 (2011).
Kabashi, E. et al. Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis. Hum. Mol. Genet. 22, 2350–2360 (2013).
Larroquette, F. et al. Vapb/Amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response. Hum. Mol. Genet. 24, 6515–6529 (2015). The VAPB-P56S knock-in model described in this report is arguably the best model of VAPB-related ALS8 as it shows evidence of neurogenic atrophy and motor impairment, probably arising from a loss of VAPB activity at the ER.
Boillee, S., Peschanski, M. & Junier, M. P. The wobbler mouse: a neurodegeneration jigsaw puzzle. Mol. Neurobiol. 28, 65–106 (2003).
Schmitt-John, T. et al. Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse. Nat. Genet. 37, 1213–1215 (2005). This paper identifies the gene mutated in wobbler mice as Vps54, connecting this classic ALS model to other models with defects in endolysosomal trafficking.
Palmisano, R. et al. Endosomal accumulation of APP in wobbler motor neurons reflects impaired vesicle trafficking: implications for human motor neuron disease. BMC Neurosci. 12, 24 (2011).
Hentati, A. et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nat. Genet. 7, 425–428 (1994).
Hosler, B. A. et al. Refined mapping and characterization of the recessive familial amyotrophic lateral sclerosis locus (ALS2) on chromosome 2q33. Neurogenetics 2, 34–42 (1998).
Hadano, S. et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat. Genet. 29, 166–173 (2001).
Yang, Y. et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat. Genet. 29, 160–165 (2001).
Topp, J. D., Gray, N. W., Gerard, R. D. & Horazdovsky, B. F. Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor. J. Biol. Chem. 279, 24612–24623 (2004).
Hadano, S. et al. Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking. Hum. Mol. Genet. 15, 233–250 (2006).
Devon, R. S. et al. Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proc. Natl Acad. Sci. USA 103, 9595–9600 (2006).
Otomo, A. et al. ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Hum. Mol. Genet. 12, 1671–1687 (2003).
Cai, H. et al. ALS2/alsin knockout mice and motor neuron diseases. Neurodegener. Dis. 5, 359–366 (2008).
Yamanaka, K. et al. Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease. Proc. Natl Acad. Sci. USA 100, 16041–16046 (2003).
Sato, K. et al. Altered oligomeric states in pathogenic ALS2 variants associated with juvenile motor neuron diseases cause loss of ALS2-mediated endosomal function. J. Biol. Chem. 293, 17135–17153 (2018).
Otomo, A., Kunita, R., Suzuki-Utsunomiya, K., Ikeda, J. E. & Hadano, S. Defective relocalization of ALS2/alsin missense mutants to Rac1-induced macropinosomes accounts for loss of their cellular function and leads to disturbed amphisome formation. FEBS Lett. 585, 730–736 (2011).
Panzeri, C. et al. The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. Brain 129, 1710–1719 (2006).
Cai, H. et al. Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knock-out mice but predisposes neurons to oxidative stress. J. Neurosci. 25, 7567–7574 (2005).
Yamanaka, K., Miller, T. M., McAlonis-Downes, M., Chun, S. J. & Cleveland, D. W. Progressive spinal axonal degeneration and slowness in ALS2-deficient mice. Ann. Neurol. 60, 95–104 (2006). This paper describes one of multiple Als2 knockout mice that have been developed over the years but also points out that the reason these models show only mild phenotypes may be due to intrinsic differences in the architecture of mouse and human upper motor neurons.
Julien, J. P. & Kriz, J. Transgenic mouse models of amyotrophic lateral sclerosis. Biochim. Biophys. Acta 1762, 1013–1024 (2006).
Gros-Louis, F. et al. Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish. Hum. Mol. Genet. 17, 2691–2702 (2008).
Hadano, S. et al. Genetic background and gender effects on gross phenotypes in congenic lines of ALS2/alsin-deficient mice. Neurosci. Res. 68, 131–136 (2010).
Deng, H. X. et al. Distal axonopathy in an alsin-deficient mouse model. Hum. Mol. Genet. 16, 2911–2920 (2007).
Gautam, M. et al. Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms. Hum. Mol. Genet. 25, 1074–1087 (2016).
Chow, C. Y. et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 448, 68–72 (2007). This paper links a spontaneous mouse mutant called the ‘pale tremor’ mice to mutations in FIG4 and neurodegenerative disease; the phenotypes seen in this mouse would later inspire the same group to link this gene to ALS.
Kunita, R. et al. Homo-oligomerization of ALS2 through its unique carboxyl-terminal regions is essential for the ALS2-associated Rab5 guanine nucleotide exchange activity and its regulatory function on endosome trafficking. J. Biol. Chem. 279, 38626–38635 (2004).
Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806–808 (2005).
Ferguson, C. J. et al. Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration. Hum. Mol. Genet. 21, 3525–3534 (2012).
Chow, C. Y. et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am. J. Hum. Genet. 84, 85–88 (2009).
Lenk, G. M. et al. Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J. PLoS Genet. 7, e1002104 (2011).
Orlacchio, A. et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 133, 591–598 (2010).
Denora, P. S. et al. Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions. Brain 139, 1723–1734 (2016).
Daoud, H. et al. Exome sequencing reveals SPG11 mutations causing juvenile ALS. Neurobiol. Aging 33, 839.e5–839.e9 (2012).
Chang, J., Lee, S. & Blackstone, C. Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. J. Clin. Invest. 124, 5249–5262 (2014).
Varga, R. E. et al. In vivo evidence for lysosome depletion and impaired autophagic clearance in hereditary spastic paraplegia type SPG11. PLoS Genet. 11, e1005454 (2015).
Boutry, M. et al. Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis. Commun. Biol. 2, 380 (2019).
Boutry, M. et al. Inhibition of lysosome membrane recycling causes accumulation of gangliosides that contribute to neurodegeneration. Cell Rep. 23, 3813–3826 (2018).
Branchu, J. et al. Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration. Neurobiol. Dis. 102, 21–37 (2017). Of the different Spg11-knockout models generated, this model showed phenotypes reminiscent of both HSP and ALS.
Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499–503 (2012).
Alkam, D., Feldman, E. Z., Singh, A. & Kiaei, M. Profilin1 biology and its mutation, actin(g) in disease. Cell Mol. Life Sci. 74, 967–981 (2017).
Boopathy, S. et al. Structural basis for mutation-induced destabilization of profilin 1 in ALS. Proc. Natl Acad. Sci. USA 112, 7984–7989 (2015).
Nekouei, M. et al. Changes in biophysical characteristics of PFN1 due to mutation causing amyotrophic lateral sclerosis. Metab. Brain Dis. 33, 1975–1984 (2018).
Kiaei, M. et al. ALS-causing mutations in profilin-1 alter its conformational dynamics: a computational approach to explain propensity for aggregation. Sci. Rep. 8, 13102 (2018).
Smith, B. N. et al. Novel mutations support a role for Profilin 1 in the pathogenesis of ALS. Neurobiol. Aging 36, 1602.e17–1602.e27 (2015).
Tanaka, Y. & Hasegawa, M. Profilin 1 mutants form aggregates that induce accumulation of prion-like TDP-43. Prion 10, 283–289 (2016).
Del Poggetto, E. et al. Stability of an aggregation-prone partially folded state of human profilin-1 correlates with aggregation propensity. J. Biol. Chem. 293, 10303–10313 (2018).
Fil, D. et al. Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease. Hum. Mol. Genet. 26, 686–701 (2017). While not the first transgenic mutant PFN1 model to show ALS-like phenotypes, this model also reported TDP43 proteinopathy and argued that these phenotypes arise via a gain-of-function mechanism.
Yang, C. et al. Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity. Proc. Natl Acad. Sci. USA 113, E6209–E6218 (2016).
Brettle, M. et al. Developmental expression of mutant PFN1 in motor neurons impacts neuronal growth and motor performance of young and adult mice. Front. Mol. Neurosci. 12, 231 (2019).
Tovar, Y. R. L. B., Zepeda, A. & Tapia, R. Vascular endothelial growth factor prevents paralysis and motoneuron death in a rat model of excitotoxic spinal cord neurodegeneration. J. Neuropathol. Exp. Neurol. 66, 913–922 (2007).
Al-Saif, A., Al-Mohanna, F. & Bohlega, S. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann. Neurol. 70, 913–919 (2011).
Kim, H. J. et al. Mutations in UBQLN2 and SIGMAR1 genes are rare in Korean patients with amyotrophic lateral sclerosis. Neurobiol. Aging 35, 1957.e7–1957.e8 (2014).
Ullah, M. I. et al. In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia. Neurogenetics 16, 299–306 (2015).
Hayashi, T. & Su, T. P. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131, 596–610 (2007).
Tagashira, H., Shinoda, Y., Shioda, N. & Fukunaga, K. Methyl pyruvate rescues mitochondrial damage caused by SIGMAR1 mutation related to amyotrophic lateral sclerosis. Biochim. Biophys. Acta 1840, 3320–3334 (2014).
Dreser, A. et al. The ALS-linked E102Q mutation in Sigma receptor-1 leads to ER stress-mediated defects in protein homeostasis and dysregulation of RNA-binding proteins. Cell Death Differ. 24, 1655–1671 (2017).
Prause, J. et al. Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis. Hum. Mol. Genet. 22, 1581–1600 (2013).
Ryskamp, D. A., Korban, S., Zhemkov, V., Kraskovskaya, N. & Bezprozvanny, I. Neuronal Sigma-1 receptors: signaling functions and protective roles in neurodegenerative diseases. Front. Neurosci. 13, 862 (2019).
Weng, T. Y., Tsai, S. A. & Su, T. P. Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases. J. Biomed. Sci. 24, 74 (2017).
Bernard-Marissal, N., Medard, J. J., Azzedine, H. & Chrast, R. Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration. Brain 138, 875–890 (2015).
Penas, C. et al. Sigma receptor agonist 2-(4-morpholinethyl)1 phenylcyclohexanecarboxylate (Pre084) increases GDNF and BiP expression and promotes neuroprotection after root avulsion injury. J. Neurotrauma 28, 831–840 (2011).
Goyagi, T. et al. Potent sigma 1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine provides ischemic neuroprotection without altering dopamine accumulation in vivo in rats. Anesth. Analg. 96, 532–538 (2003).
Guzman-Lenis, M. S., Navarro, X. & Casas, C. Selective sigma receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE084) promotes neuroprotection and neurite elongation through protein kinase C (PKC) signaling on motoneurons. Neuroscience 162, 31–38 (2009).
Mancuso, R. et al. Sigma-1R agonist improves motor function and motoneuron survival in ALS mice. Neurotherapeutics 9, 814–826 (2012).
Peviani, M. et al. Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation. Neurobiol. Dis. 62, 218–232 (2014).
Ono, Y. et al. SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models. Neurosci. Lett. 559, 174–178 (2014).
Ionescu, A. et al. Targeting the sigma-1 receptor via pridopidine ameliorates central features of ALS pathology in a SOD1(G93A) model. Cell Death Dis. 10, 210 (2019).
Mavlyutov, T. A., Epstein, M. L., Andersen, K. A., Ziskind-Conhaim, L. & Ruoho, A. E. The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons: an anatomical and behavioral study. Neuroscience 167, 247–255 (2010).
Sabino, V., Cottone, P., Parylak, S. L., Steardo, L. & Zorrilla, E. P. Sigma-1 receptor knockout mice display a depressive-like phenotype. Behav. Brain Res. 198, 472–476 (2009).
Chevallier, N., Keller, E. & Maurice, T. Behavioural phenotyping of knockout mice for the sigma-1 (σ1) chaperone protein revealed gender-related anxiety, depressive-like and memory alterations. J. Psychopharmacol. 25, 960–975 (2011).
Mavlyutov, T. A. et al. Lack of sigma-1 receptor exacerbates ALS progression in mice. Neuroscience 240, 129–134 (2013).
Watanabe, S. et al. Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS. EMBO Mol. Med. 8, 1421–1437 (2016). While a previous study had shown that knocking out Sigmar1 in an SOD1 mouse model could impact disease-related phenotypes, this study found that it may accelerate disease onset by impacting ER-mitochondrial connections at the MAM — connecting this gene to other reports of MAM collapse in ALS.
Stoica, R. et al. ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat. Commun. 5, 3996 (2014).
Sakai, S., Watanabe, S., Komine, O., Sobue, A. & Yamanaka, K. Novel reporters of mitochondria-associated membranes (MAM), MAMtrackers, demonstrate MAM disruption as a common pathological feature in amyotrophic lateral sclerosis. FASEB J. 35, e21688 (2021).
Mitchell, J. et al. Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase. Proc. Natl Acad. Sci. USA 107, 7556–7561 (2010).
Padhi, A. K. & Hazra, S. Insights into the role of d-amino acid oxidase mutations in amyotrophic lateral sclerosis. J. Cell Biochem. https://doi.org/10.1002/jcb.27529 (2018).
Sasabe, J. et al. D-serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. EMBO J. 26, 4149–4159 (2007).
Wu, S. & Barger, S. W. Induction of serine racemase by inflammatory stimuli is dependent on AP-1. Ann. NY Acad. Sci. 1035, 133–146 (2004).
Paul, P., Murphy, T., Oseni, Z., Sivalokanathan, S. & de Belleroche, J. S. Pathogenic effects of amyotrophic lateral sclerosis-linked mutation in D-amino acid oxidase are mediated by D-serine. Neurobiol. Aging 35, 876–885 (2014).
Sasabe, J., Suzuki, M., Imanishi, N. & Aiso, S. Activity of D-amino acid oxidase is widespread in the human central nervous system. Front. Synaptic Neurosci. 6, 14 (2014).
Almond, S. L. et al. Behavioral and biochemical characterization of a mutant mouse strain lacking D-amino acid oxidase activity and its implications for schizophrenia. Mol. Cell Neurosci. 32, 324–334 (2006).
Sasabe, J. et al. D-amino acid oxidase controls motoneuron degeneration through D-serine. Proc. Natl Acad. Sci. USA 109, 627–632 (2012).
Kondori, N. R. et al. Focus on the role of d-serine and d-amino acid oxidase in amyotrophic lateral sclerosis/motor neuron disease (ALS). Front. Mol. Biosci. 5, 8 (2018). This article reports the only model to express a known ALS-associated mutation in DAO; other studies have relied on a spontaneous mouse mutation in this gene that also imparts a loss of function.
DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011). While not a mouse modelling paper, this is the first report, together with Renton et al. (2011), to associate the hexanucleotide repeat expansion in C9ORF72 to ALS/FTD — a major leap forward in the field of ALS research.
Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011). Together with DeJesus-Hernandez et al. (2011), the authors linked a repeat expansion in C9ORF72 to ALS and FTD — this would later prove to be the most common known genetic lesion to cause both diseases.
Majounie, E. et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 11, 323–330 (2012).
Belzil, V. V. et al. Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol. 126, 895–905 (2013).
Gijselinck, I. et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 11, 54–65 (2012).
Ciura, S. et al. Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann. Neurol. 74, 180–187 (2013).
Fratta, P. et al. Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia. Acta Neuropathol. 126, 401–409 (2013).
Dong, W. et al. Knock in of a hexanucleotide repeat expansion in the C9orf72 gene induces ALS in rats. Animal Model. Exp. Med. 3, 237–244 (2020).
Lagier-Tourenne, C. et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc. Natl Acad. Sci. USA 110, E4530–E4539 (2013).
Koppers, M. et al. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann. Neurol. 78, 426–438 (2015).
O’Rourke, J. G. et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329 (2016).
Atanasio, A. et al. C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci. Rep. 6, 23204 (2016).
Jiang, J. et al. Gain of toxicity from ALS/FTD-linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs. Neuron 90, 535–550 (2016).
Burberry, A. et al. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci. Transl Med. 8, 347ra393 (2016).
Ugolino, J. et al. Loss of C9orf72 enhances autophagic activity via deregulated mTOR and TFEB Signaling. PLoS Genet. 12, e1006443 (2016).
Burberry, A. et al. C9orf72 suppresses systemic and neural inflammation induced by gut bacteria. Nature 582, 89–94 (2020). In an elegant example of determination in research, this study solved the riddle about why different C9orf72-knockout models showed varying phenotypes: loss of C9orf72 impacts innate immunity in mice, making them sensitive to changes in their gut microbiome.
Shao, Q. et al. C9orf72 deficiency promotes motor deficits of a C9ALS/FTD mouse model in a dose-dependent manner. Acta Neuropathol. Commun. 7, 32 (2019).
Zhu, Q. et al. Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72. Nat. Neurosci. 23, 615–624 (2020).
Todd, T. W. & Petrucelli, L. Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions. J. Neurochem. 138, 145–162 (2016).
Zu, T. et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc. Natl Acad. Sci. USA 110, E4968–E4977 (2013).
Mizielinska, S. et al. C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol. 126, 845–857 (2013).
Cooper-Knock, J. et al. Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol. 130, 63–75 (2015).
Ash, P. E. et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639–646 (2013).
Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335–1338 (2013).
Gendron, T. F. et al. Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol. 126, 829–844 (2013).
Davidson, Y. S. et al. Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol. Commun. 2, 70 (2014).
Mackenzie, I. R. et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol. 126, 859–879 (2013).
Edbauer, D. & Haass, C. An amyloid-like cascade hypothesis for C9orf72 ALS/FTD. Curr. Opin. Neurobiol. 36, 99–106 (2016).
Baborie, A. et al. Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene. Neuropathol. Appl. Neurobiol. 41, 601–612 (2015).
Chew, J. et al. Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348, 1151–1154 (2015).
Chew, J. et al. Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy. Mol. Neurodegener. 14, 9 (2019). Our laboratory previously developed a viral 66-repeat model of c9FTD/ALS and found that it recapitulated features of the human disease — this report is a step forward, where we expressed an even longer 149-repeat construct, saw more robust ALS-like features and linked defects in stress granule dynamics to pTDP43 pathology.
Herranz-Martin, S. et al. Viral delivery of C9orf72 hexanucleotide repeat expansions in mice leads to repeat-length-dependent neuropathology and behavioural deficits. Dis. Model. Mech. 10, 859–868 (2017).
Riemslagh, F. W. et al. Inducible expression of human C9ORF72 36x G4C2 hexanucleotide repeats is sufficient to cause RAN translation and rapid muscular atrophy in mice. Dis. Model. Mech. 14, dmm044842 (2021).
O’Rourke, J. G. et al. C9orf72 BAC transgenic mice display typical pathologic features of ALS/FTD. Neuron 88, 892–901 (2015).
Peters, O. M. et al. Human C9ORF72 hexanucleotide expansion reproduces RNA foci and dipeptide repeat proteins but not neurodegeneration in BAC transgenic mice. Neuron 88, 902–909 (2015).
Shi, Y. et al. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat. Med. 24, 313–325 (2018).
Liu, Y. et al. C9orf72 BAC mouse model with motor deficits and neurodegenerative features of ALS/FTD. Neuron 90, 521–534 (2016). While multiple groups have developed BAC models of c9FTD/ALS, this paper documents the only one to show ALS-like motor deficits and degeneration.
Pattamatta, A. et al. Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice. Hum. Mol. Genet. 29, 3900–3918 (2021).
Mordes, D. A. et al. Absence of survival and motor deficits in 500 repeat C9ORF72 BAC mice. Neuron 108, 775–783.e4 (2020).
Nguyen, L. et al. Survival and motor phenotypes in FVB C9-500 ALS/FTD BAC transgenic mice reproduced by multiple labs. Neuron 108, 784–796.e3 (2020).
Zhang, Y. J. et al. Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nat. Med. 24, 1136–1142 (2018).
Cook, C. N. et al. C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy. Sci. Transl Med. 12, eabb3774 (2020). We and others have developed mouse models that express only poly(GR) but, in this study, we found that expression of a 200-repeat poly(GR) could induce the formation of TDP43 inclusions, linking this DPR to the development of TDP43 proteinopathy in c9FTD/ALS.
Choi, S. Y. et al. C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo. Nat. Neurosci. 22, 851–862 (2019).
Zhang, Y. J. et al. Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. Science 363, eaav2606 (2019). This mouse model, like others, demonstrates the potent toxicity of poly(PR) in vivo and also links this toxicity to defects in heterochromatin and double-stranded RNA accumulation.
Hao, Z. et al. Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR. Nat. Commun. 10, 2906 (2019).
LaClair, K. D. et al. Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS. Acta Neuropathol. 140, 121–142 (2020).
Zhang, Y. J. et al. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat. Neurosci. 19, 668–677 (2016). Poly(GA) aggregates are the most abundant DPR pathology observed in c9FTD/ALS, but this DPR often appears to be only mildly toxic in lower model organisms — this study verified that poly(GA) could induce toxicity in rodents, possibly by sequestering HR23 and nucleocytoplasmic transport factors.
Schludi, M. H. et al. Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss. Acta Neuropathol. 134, 241–254 (2017).
Khosravi, B. et al. Cell-to-cell transmission of C9orf72 poly-(Gly-Ala) triggers key features of ALS/FTD. EMBO J. 39, e102811 (2020). This paper found that poly(GA) could be transferred between cells and, in this way, it induced TDP43 pathology and other defects in neighbouring cells; inhibiting this transmission with anti-poly(GA) antibodies proved beneficial.
Todd, T. W. et al. Hexanucleotide repeat expansions in c9FTD/ALS and SCA36 confer selective patterns of neurodegeneration in vivo. Cell Rep. 31, 107616 (2020).
Hawrot, J., Imhof, S. & Wainger, B. J. Modeling cell-autonomous motor neuron phenotypes in ALS using iPSCs. Neurobiol. Dis. 134, 104680 (2020).
Burkhardt, M. F. et al. A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells. Mol. Cell Neurosci. 56, 355–364 (2013).
Fujimori, K. et al. Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent. Nat. Med. 24, 1579–1589 (2018).
Geser, F., Lee, V. M. & Trojanowski, J. Q. Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies. Neuropathology 30, 103–112 (2010).
van der Zee, J. et al. CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro. Hum. Mol. Genet. 17, 313–322 (2008).
Parkinson, N. et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 67, 1074–1077 (2006).
Cox, L. E. et al. Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS ONE 5, e9872 (2010).
van Blitterswijk, M. et al. Genetic overlap between apparently sporadic motor neuron diseases. PLoS ONE 7, e48983 (2012).
Narain, P. et al. Targeted next-generation sequencing reveals novel and rare variants in Indian patients with amyotrophic lateral sclerosis. Neurobiol. Aging 71, 265.e9–265.e14 (2018).
Ferrari, R. et al. Novel missense mutation in charged multivesicular body protein 2B in a patient with frontotemporal dementia. Alzheimer Dis. Assoc. Disord. 24, 397–401 (2010).
Ghanim, M. et al. CHMP2B mutations are rare in French families with frontotemporal lobar degeneration. J. Neurol. 257, 2032–2036 (2010).
Piper, R. C. & Luzio, J. P. Late endosomes: sorting and partitioning in multivesicular bodies. Traffic 2, 612–621 (2001).
Zhang, Y. et al. Patient iPSC-derived neurons for disease modeling of frontotemporal dementia with mutation in CHMP2B. Stem Cell Rep. 8, 648–658 (2017).
Han, J. H., Ryu, H. H., Jun, M. H., Jang, D. J. & Lee, J. A. The functional analysis of the CHMP2B missense mutation associated with neurodegenerative diseases in the endo-lysosomal pathway. Biochem. Biophys. Res. Commun. 421, 544–549 (2012).
Blair, I. P. et al. CHMP2B mutations are not a common cause of familial or sporadic amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 79, 849–850 (2008).
Isaacs, A. M., Johannsen, P., Holm, I. & Nielsen, J. E., FReJA Consortium. Frontotemporal dementia caused by CHMP2B mutations. Curr. Alzheimer Res. 8, 246–251 (2011).
Lee, J. A., Beigneux, A., Ahmad, S. T., Young, S. G. & Gao, F. B. ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr. Biol. 17, 1561–1567 (2007).
Ghazi-Noori, S. et al. Progressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice. Brain 135, 819–832 (2012).
Clayton, E. L. et al. Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation. Hum. Mol. Genet. 26, 873–887 (2017).
Gascon, E. et al. Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia. Nat. Med. 20, 1444–1451 (2014).
Vernay, A. et al. A transgenic mouse expressing CHMP2Bintron5 mutant in neurons develops histological and behavioural features of amyotrophic lateral sclerosis and frontotemporal dementia. Hum. Mol. Genet. 25, 3341–3360 (2016). Mutations in CHMP2B are often associated with FTD, but this transgenic mouse model also saw evidence of ALS-like phenotypes.
Bannwarth, S. et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 137, 2329–2345 (2014).
Genin, E. C. et al. Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases. Neurobiol. Dis. 119, 159–171 (2018).
Ait-El-Mkadem Saadi, S. et al. CHCHD10-Related Disorders (eds Adam, M. P. et al.) (GeneReviews, 2015).
van Rheenen, W., Diekstra, F. P., van den Berg, L. H. & Veldink, J. H. Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis? Brain 137, e313 (2014).
Project MinE ALS Sequencing Consortium. CHCHD10 variants in amyotrophic lateral sclerosis: where is the evidence? Ann. Neurol. 84, 110–116 (2018).
Burstein, S. R. et al. In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions. Hum. Mol. Genet. 27, 160–177 (2018).
Anderson, C. J. et al. ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response. Acta Neuropathol. 138, 103–121 (2019).
Genin, E. C. et al. Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse. Acta Neuropathol. 138, 123–145 (2019).
Ryan, E. B. et al. Early death of ALS-linked CHCHD10-R15L transgenic mice with central nervous system, skeletal muscle, and cardiac pathology. iScience 24, 102061 (2021).
Xiao, Y. et al. Loss of mitochondrial protein CHCHD10 in skeletal muscle causes neuromuscular junction impairment. Hum. Mol. Genet. 29, 1784–1796 (2020).
Hideyama, T. et al. Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. J. Neurosci. 30, 11917–11925 (2010).
Beaulieu, J. M., Nguyen, M. D. & Julien, J. P. Late onset of motor neurons in mice overexpressing wild-type peripherin. J. Cell Biol. 147, 531–544 (1999).
Beaulieu, J. M., Jacomy, H. & Julien, J. P. Formation of intermediate filament protein aggregates with disparate effects in two transgenic mouse models lacking the neurofilament light subunit. J. Neurosci. 20, 5321–5328 (2000).
Ash, P. E. A. et al. Heavy metal neurotoxicants induce ALS-linked TDP-43 pathology. Toxicol. Sci. 167, 105–115 (2019).
Maya, S., Prakash, T. & Goli, D. Evaluation of neuroprotective effects of wedelolactone and gallic acid on aluminium-induced neurodegeneration: relevance to sporadic amyotrophic lateral sclerosis. Eur. J. Pharmacol. 835, 41–51 (2018).
Nampoothiri, M. et al. Modulatory role of simvastatin against aluminium chloride-induced behavioural and biochemical changes in rats. Behav. Neurol. 2015, 210169 (2015).
Shaw, C. A. & Petrik, M. S. Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J. Inorg. Biochem. 103, 1555–1562 (2009).
de Munck, E. et al. beta-N-methylamino-l-alanine causes neurological and pathological phenotypes mimicking amyotrophic lateral sclerosis (ALS): the first step towards an experimental model for sporadic ALS. Env. Toxicol. Pharmacol. 36, 243–255 (2013).
Yin, H. Z. et al. Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord. Exp. Neurol. 261, 1–9 (2014).
de Munck, E. et al. Morphometric and neurochemical alterations found in l-BMAA treated rats. Env. Toxicol. Pharmacol. 39, 1232–1245 (2015).
Tian, K. W., Jiang, H., Wang, B. B., Zhang, F. & Han, S. Intravenous injection of l-BMAA induces a rat model with comprehensive characteristics of amyotrophic lateral sclerosis/Parkinson-dementia complex. Toxicol. Res. 5, 79–96 (2016).
Scott, L. L. & Downing, T. G. A single neonatal exposure to BMAA in a rat model produces neuropathology consistent with neurodegenerative diseases. Toxins 10, 22 (2017).
Papapetropoulos, S. Is there a role for naturally occurring cyanobacterial toxins in neurodegeneration? The beta-N-methylamino-L-alanine (BMAA) paradigm. Neurochem. Int. 50, 998–1003 (2007).
Mishra, P. S. et al. Transmission of ALS pathogenesis by the cerebrospinal fluid. Acta Neuropathol. Commun. 8, 65 (2020).
Muchnik, S., Losavio, A. & De Lorenzo, S. Effect of amyotrophic lateral sclerosis serum on calcium channels related to spontaneous acetylcholine release. Clin. Neurophysiol. 113, 1066–1071 (2002).
Obal, I. et al. Experimental motor neuron disease induced in mice with long-term repeated intraperitoneal injections of serum from ALS patients. Int. J. Mol. Sci. 20, 2573 (2019).
Shanmukha, S., Narayanappa, G., Nalini, A., Alladi, P. A. & Raju, T. R. Sporadic amyotrophic lateral sclerosis (SALS) - skeletal muscle response to cerebrospinal fluid from SALS patients in a rat model. Dis. Model Mech. 11, dmm031997 (2018).
Ikebe, S. et al. Increase of deleted mitochondrial DNA in the striatum in Parkinson’s disease and senescence. Biochem. Biophys. Res. Commun. 170, 1044–1048 (1990).
Sankaranarayani, R., Nalini, A., Rao Laxmi, T. & Raju, T. R. Altered neuronal activities in the motor cortex with impaired motor performance in adult rats observed after infusion of cerebrospinal fluid from amyotrophic lateral sclerosis patients. Behav. Brain Res. 206, 109–119 (2010).
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Glossary
- Inclusion
-
An abnormal accumulation of insoluble, misfolded proteins that can be observed by histochemistry in cells and is often a hallmark of disease.
- Knock-in model
-
An animal model in which researchers have replaced all or part a specific endogenous gene with transgenic sequences.
- Knockout models
-
Animal models in which researchers have disrupted a gene of interest by replacing all or part of the gene with another piece of DNA.
- Proteinopathy
-
A disease in which certain proteins misfold or aggregate.
- Prion-like domain
-
Named after the prion protein, these are unstructured domains that can adopt different conformations in response to environmental cues and ‘pass on’ this conformation to other proteins through self-propagation.
- Neuroinflammation
-
An inflammatory response within the brain or spinal cord, generally regulated by resident microglia and astrocytes.
- Rotarod test
-
A behavioural test for rodents that measures locomotor function by measuring how long animals can run on an accelerating, rotating rod within a set time limit.
- Dominant negative effect
-
A situation in which a mutant protein negatively impacts the function of its wild-type counterparts within the same cell.
- Kyphosis
-
Curvature of the spine.
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Todd, T.W., Petrucelli, L. Modelling amyotrophic lateral sclerosis in rodents. Nat Rev Neurosci 23, 231–251 (2022). https://doi.org/10.1038/s41583-022-00564-x
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DOI: https://doi.org/10.1038/s41583-022-00564-x
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