Amyotrophic lateral sclerosis (ALS) is a genetically diverse disease. At least 15 ALS-associated gene loci have so far been identified, and the causative gene is known in approximately 30% of familial ALS cases. Less is known about the factors underlying the sporadic form of the disease. The molecular mechanisms of motor neuron degeneration are best understood in the subtype of disease caused by mutations in superoxide dismutase 1, with a current consensus that motor neuron injury is caused by a complex interplay between multiple pathogenic processes. A key recent finding is that mutated TAR DNA-binding protein 43 is a major constituent of the ubiquitinated protein inclusions in ALS, providing a possible link between the genetic mutation and the cellular pathology. New insights have also indicated the importance of dysregulated glial cell–motor neuron crosstalk, and have highlighted the vulnerability of the distal axonal compartment early in the disease course. In addition, recent studies have suggested that disordered RNA processing is likely to represent a major contributing factor to motor neuron disease. Ongoing research on the cellular pathways highlighted in this Review is predicted to open the door to new therapeutic interventions to slow disease progression in ALS.
Multiple cellular events contribute to the pathobiology of amyotrophic lateral sclerosis (ALS), including oxidative stress, mitochondrial dysfunction, excitotoxicity, protein aggregation, impaired axonal transport, neuroinflammation, and dysregulated RNA signaling
TAR DNA-binding protein 43 is a major constituent of the ubiquitinated protein inclusions found in surviving motor neurons in most forms of ALS
Glial pathology and disruption of glial cell–motor neuron communication contribute to neurodegeneration and the propagation of motor neuron injury
Understanding the links between molecular changes and clinical features of the disease should guide future therapeutic efforts
Degenerative changes in motor neurons seem to affect the health of the distal axonal compartment at an early stage of disease, highlighting an important neuroprotective target
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Wood-Allum, C. & Shaw, P. J. Motor neurone disease: a practical update on diagnosis and management. Clin. Med. 10, 252–258 (2010).
Ince, P. G., Clark, B., Holton, J., Revesz, T. & Wharton, S. B. in Greenfield's Neuropathology (eds Love, S. et al.) 947–971 (Hodder Arnold, London, 2008).
Martin, L. J. Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. J. Neuropathol. Exp. Neurol. 58, 459–471 (1999).
Ince, P. G., Lowe, J. & Shaw, P. J. Amyotrophic lateral sclerosis: current issues in classification, pathogenesis and molecular pathology. Neuropathol. Appl. Neurobiol. 24, 104–117 (1998).
Ince, P. G., Tomkins, J., Slade, J. Y., Thatcher, N. M. & Shaw, P. J. Amyotrophic lateral sclerosis associated with genetic abnormalities in the gene encoding Cu/Zn superoxide dismutase: molecular pathology of five new cases, and comparison with previous reports and 73 sporadic cases of ALS. J. Neuropathol. Exp. Neurol. 57, 895–904 (1998).
Piao, Y. S. et al. Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000. Brain Pathol. 13, 10–22 (2003).
Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
Nishihara, Y. et al. Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43 immunoreactive neuronal and glial cytoplasmic inclusions. Acta Neuropathol. 116, 169–182 (2008).
Zhang, H. et al. TDP-43 immunoreactive neuronal and glial inclusions in the neostriatum in amyotrophic lateral sclerosis with and without dementia. Acta Neuropathol. 115, 115–122 (2008).
Ilieva, H., Polymenidou, M. & Cleveland, D. W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761–772 (2009).
Kirby, J. et al. Mutant SOD1 alters the motor neuronal transcriptome: implications for familial ALS. Brain 128, 1686–1706 (2005).
Kirby, J. et al. Phosphatase and tensin homologue/protein kinase B pathway linked to motor neuron survival in human superoxide dismutase 1-related amyotrophic lateral sclerosis. Brain 134, 506–517 (2011).
Tovar, Y. R. & Tapia, R. VEGF protects spinal motor neurons against chronic excitotoxic degeneration in vivo by activation of PI3-K pathway and inhibition of p38 MAPK. J. Neurochem. 115, 1090–1101 (2010).
Brockington, A. et al. Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGFδ/δ mouse model of amyotrophic lateral sclerosis. BMC Genomics 11, 203 (2010).
Murray, L. M., Talbot, K. & Gillingwater, T. H. Review: neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophy. Neuropathol. Appl. Neurobiol. 36, 133–156 (2010).
Aggarwal, S. & Cudkowicz, M. ALS drug development: reflections of the past and a way forward. Neurotherapeutics 5, 516–527 (2008).
Schnabel, J. Neuroscience: standard model. Nature 454, 682–685 (2008).
Schymick, J. C., Talbot, K. & Traynor, B. J. Genetics of sporadic amyotrophic lateral sclerosis. Hum. Mol. Genet. 16 (Spec. no. 2), R233–R242 (2007).
Dunckley, T. et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N. Engl. J. Med. 357, 775–788 (2007).
van Es, M. A. et al. ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study. Lancet Neurol. 6, 869–877 (2007).
van Es, M. A. et al. Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis. Nat. Genet. 40, 29–31 (2008).
Laaksovirta, H. et al. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 9, 978–985 (2010).
Shatunov, A. et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol. 9, 986–994 (2010).
Hosler, B. A. et al. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 284, 1664–1669 (2000).
Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010).
Andersen, P. M. & Al-Chalabi, A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat. Rev. Neurol. 7, 603–615 (2011).
Rosen, D. R. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 364, 362 (1993).
Smith, R. G., Henry, Y. K., Mattson, M. P. & Appel, S. H. Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. Ann. Neurol. 44, 696–699 (1998).
Simpson, E. P., Henry, Y. K., Henkel, J. S., Smith, R. G. & Appel, S. H. Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology 62, 1758–1765 (2004).
Mitsumoto, H. et al. Oxidative stress biomarkers in sporadic ALS. Amyotroph. Lateral Scler. 9, 177–183 (2008).
Shaw, P. J., Ince, P. G., Falkous, G. & Mantle, D. Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann. Neurol. 38, 691–695 (1995).
Shibata, N. et al. Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients. Brain Res. 917, 97–104 (2001).
Fitzmaurice, P. S. et al. Evidence for DNA damage in amyotrophic lateral sclerosis. Muscle Nerve 19, 797–798 (1996).
Chang, Y. et al. Messenger RNA oxidation occurs early in disease pathogenesis and promotes motor neuron degeneration in ALS. PLoS ONE 3, e2849 (2008).
Barber, S. C. & Shaw, P. J. Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radic. Biol. Med. 48, 629–641 (2010).
Andrus, P. K., Fleck, T. J., Gurney, M. E. & Hall, E. D. Protein oxidative damage in a transgenic mouse model of familial amyotrophic lateral sclerosis. J. Neurochem. 71, 2041–2048 (1998).
Duan, W. et al. Mutant TAR DNA-binding protein-43 induces oxidative injury in motor neuron-like cell. Neuroscience 169, 1621–1629 (2010).
Subramaniam, J. R. et al. Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading. Nat. Neurosci. 5, 301–307 (2002).
Harraz, M. M. et al. SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J. Clin. Invest. 118, 659–670 (2008).
Wu, D. C., Re, D. B., Nagai, M., Ischiropoulos, H. & Przedborski, S. The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proc. Natl Acad. Sci. USA 103, 12132–12137 (2006).
Marden, J. J. et al. Redox modifier genes in amyotrophic lateral sclerosis in mice. J. Clin. Invest. 117, 2913–2919 (2007).
Sarlette, A. et al. Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 67, 1055–1062 (2008).
Rao, S. D. & Weiss, J. H. Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis. Trends Neurosci. 27, 17–23 (2004).
Duffy, L. M. et al. The role of mitochondria in the pathogenesis of amyotrophic lateral sclerosis. Neuropathol. Appl. Neurobiol. 37, 336–352 (2011).
Wood, J. D., Beaujeux, T. P. & Shaw, P. J. Protein aggregation in motor neurone disorders. Neuropathol. Appl. Neurobiol. 29, 529–545 (2003).
Kanekura, K., Suzuki, H., Aiso, S. & Matsuoka, M. ER stress and unfolded protein response in amyotrophic lateral sclerosis. Mol. Neurobiol. 39, 81–89 (2009).
Blackburn, D., Sargsyan, S., Monk, P. N. & Shaw, P. J. Astrocyte function and role in motor neuron disease: a future therapeutic target? Glia 57, 1251–1264 (2009).
Sargsyan, S. A., Monk, P. N. & Shaw, P. J. Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis. Glia 51, 241–253 (2005).
Benatar, M. Lost in translation: treatment trials in the SOD1 mouse and in human ALS. Neurobiol. Dis. 26, 1–13 (2007).
Orrell, R. W., Lane, R. J. & Ross, M. Antioxidant treatment for amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD002829. http://dx.doi.org/10.1002/14651858.CD002829.pub4 (2007).
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).
Liu, J. et al. Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron 43, 5–17 (2004).
Pasinelli, P. et al. Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron 43, 19–30 (2004).
Vande Velde, C., Miller, T. M., Cashman, N. R. & Cleveland, D. W. Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc. Natl Acad. Sci. USA 105, 4022–4027 (2008).
Wiedemann, F. R., Manfredi, G., Mawrin, C., Beal, M. F. & Schon, E. A. Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. J. Neurochem. 80, 616–625 (2002).
Mattiazzi, M. et al. Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J. Biol. Chem. 277, 29626–29633 (2002).
Damiano, M. et al. Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice. J. Neurochem. 96, 1349–1361 (2006).
Grosskreutz, J., Van Den Bosch, L. & Keller, B. U. Calcium dysregulation in amyotrophic lateral sclerosis. Cell Calcium 47, 165–174 (2010).
Sathasivam, S., Grierson, A. J. & Shaw, P. J. Characterization of the caspase cascade in a cell culture model of SOD1-related familial amyotrophic lateral sclerosis: expression, activation and therapeutic effects of inhibition. Neuropathol. Appl. Neurobiol. 31, 467–485 (2005).
Sasaki, S. & Iwata, M. Mitochondrial alterations in the spinal cord of patients with sporadic amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 66, 10–16 (2007).
Menzies, F. M. et al. Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis. Brain 125, 1522–1533 (2002).
De Vos, K. J. et al. Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Hum. Mol. Genet. 16, 2720–2728 (2007).
De Vos, K. J., Grierson, A. J., Ackerley, S. & Miller, C. C. Role of axonal transport in neurodegenerative diseases. Annu. Rev. Neurosci. 31, 151–173 (2008).
Bordet, T. et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J. Pharmacol. Exp. Ther. 322, 709–720 (2007).
Van Damme, P., Dewil, M., Robberecht, W. & Van Den Bosch, L. Excitotoxicity and amyotrophic lateral sclerosis. Neurodegener. Dis. 2, 147–159 (2005).
Arundine, M. & Tymianski, M. Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium 34, 325–337 (2003).
Carriedo, S. G., Yin, H. Z. & Weiss, J. H. Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro. J. Neurosci. 16, 4069–4079 (1996).
King, A. E. et al. Excitotoxicity mediated by non-NMDA receptors causes distal axonopathy in long-term cultured spinal motor neurons. Eur. J. Neurosci. 26, 2151–2159 (2007).
Williams, T. L., Day, N. C., Ince, P. G., Kamboj, R. K. & Shaw, P. J. Calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis. Ann. Neurol. 42, 200–207 (1997).
Ince, P. et al. Parvalbumin and calbindin D-28k in the human motor system and in motor neuron disease. Neuropathol. Appl. Neurobiol. 19, 291–299 (1993).
Shaw, P. J., Forrest, V., Ince, P. G., Richardson, J. P. & Wastell, H. J. CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration 4, 209–216 (1995).
Rothstein, J. D., Martin, L. J. & Kuncl, R. W. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N. Engl. J. Med. 326, 1464–1468 (1992).
Rothstein, J. D., Van Kammen, M., Levey, A. I., Martin, L. J. & Kuncl, R. W. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol. 38, 73–84 (1995).
Fray, A. E. et al. The expression of the glial glutamate transporter protein EAAT2 in motor neuron disease: an immunohistochemical study. Eur. J. Neurosci. 10, 2481–2489 (1998).
Foran, E. & Trotti, D. Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxid. Redox Signal. 11, 1587–1602 (2009).
Vucic, S., Nicholson, G. A. & Kiernan, M. C. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 131, 1540–1550 (2008).
Vucic, S. & Kiernan, M. C. Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. Brain 129, 2436–2446 (2006).
Kwak, S., Hideyama, T., Yamashita, T. & Aizawa, H. AMPA receptor-mediated neuronal death in sporadic ALS. Neuropathology 30, 182–188 (2010).
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).
Meehan, C. F. et al. Intrinsic properties of lumbar motor neurones in the adult G127insTGGG superoxide dismutase-1 mutant mouse in vivo: evidence for increased persistent inward currents. Acta Physiol. 200, 361–376 (2010).
Boston-Howes, W. et al. Caspase-3 cleaves and inactivates the glutamate transporter EAAT2. J. Biol. Chem. 281, 14076–14084 (2006).
Milanese, M. et al. Abnormal exocytotic release of glutamate in a mouse model of amyotrophic lateral sclerosis. J. Neurochem. 116, 1028–1042 (2011).
Sunico, C. R. et al. Reduction in the motoneuron inhibitory/excitatory synaptic ratio in an early-symptomatic mouse model of amyotrophic lateral sclerosis. Brain Pathol. 21, 1–15 (2011).
Van Damme, P. et al. Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proc. Natl Acad. Sci. USA 104, 14825–14830 (2007).
Cheah, B. C., Vucic, S., Krishnan, A. V. & Kiernan, M. C. Riluzole, neuroprotection and amyotrophic lateral sclerosis. Curr. Med. Chem. 17, 1942–1959 (2010).
Lacomblez, L., Bensimon, G., Leigh, P. N., Guillet, P. & Meininger, V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 347, 1425–1431 (1996).
Siciliano, G. et al. Clinical trials for neuroprotection in ALS. CNS Neurol. Disord. Drug Targets. 9, 305–313 (2010).
Giordana, M. T. et al. TDP-43 redistribution is an early event in sporadic amyotrophic lateral sclerosis. Brain Pathol. 20, 351–360 (2010).
Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).
Sobue, G. et al. Phosphorylated high molecular weight neurofilament protein in lower motor neurons in amyotrophic lateral sclerosis and other neurodegenerative diseases involving ventral horn cells. Acta Neuropathol. 79, 402–408 (1990).
Okamoto, K., Hirai, S., Amari, M., Watanabe, M. & Sakurai, A. Bunina bodies in amyotrophic lateral sclerosis immunostained with rabbit anti-cystatin C serum. Neurosci. Lett. 162, 125–128 (1993).
Shibata, N. et al. Cu/Zn superoxide dismutase-like immunoreactivity in Lewy body-like inclusions of sporadic amyotrophic lateral sclerosis. Neurosci. Lett. 179, 149–152 (1994).
Rakhit, R. et al. An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS. Nat. Med. 13, 754–759 (2007).
Bosco, D. A. et al. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat. Neurosci. 13, 1396–1403 (2010).
Groen, E. J. et al. FUS mutations in familial amyotrophic lateral sclerosis in the Netherlands. Arch. Neurol. 67, 224–230 (2010).
Hewitt, C. et al. Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 67, 455–461 (2010).
Ackerley, S. et al. Glutamate slows axonal transport of neurofilaments in transfected neurons. J. Cell Biol. 150, 165–176 (2000).
Ackerley, S. et al. Neurofilament heavy chain side arm phosphorylation regulates axonal transport of neurofilaments. J. Cell Biol. 161, 489–495 (2003).
Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857–864 (2010).
Ritson, G. P. et al. TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. J. Neurosci. 30, 7729–7739 (2010).
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).
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).
Lai, C. et al. 2006. Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking. J. Neurosci. 26, 11798–11806 (2006).
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).
Maruyama, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465, 223–226 (2010).
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).
Chow, C. Y. et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am. J. Hum. Genet. 84, 85–88 (2009).
Michell, R. H. & Dove, S. K. A protein complex that regulates PtdIns(3,5)P2 levels. EMBO J. 28, 86–87 (2009).
Kieran, D. et al. A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice. J. Cell Biol. 169, 561–567 (2005).
Williamson, T. L. & Cleveland, D. W. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat. Neurosci. 2, 50–56 (1999).
Bilsland, L. G. et al. Deficits in axonal transport precede ALS symptoms in vivo. Proc. Natl Acad. Sci. USA 107, 20523–20528 (2010).
Miller, K. E. & Sheetz, M. P. Axonal mitochondrial transport and potential are correlated. J. Cell Sci. 117, 2791–2804 (2004).
Kiaei, M. et al. Matrix metalloproteinase-9 regulates TNF-α and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis. Exp. Neurol. 205, 74–81 (2007).
De Vos, K. et al. Tumor necrosis factor induces hyperphosphorylation of kinesin light chain and inhibits kinesin-mediated transport of mitochondria. J. Cell Biol. 149, 1207–1214 (2000).
Ackerley, S. et al. p38α stress-activated protein kinase phosphorylates neurofilaments and is associated with neurofilament pathology in amyotrophic lateral sclerosis. Mol. Cell Neurosci. 26, 354–364 (2004).
Tortarolo, M. et al. Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression. Mol. Cell Neurosci. 23, 180–192 (2003).
Brownlees, J. et al. Phosphorylation of neurofilament heavy chain side-arms by stress activated protein kinase-1b/Jun N-terminal kinase-3. J. Cell Sci. 113, 401–407 (2000).
Guidato, S., Tsai, L. H., Woodgett, J. & Miller, C. C. Differential cellular phosphorylation of neurofilament heavy side-arms by glycogen synthase kinase-3 and cyclin-dependent kinase-5. J. Neurochem. 66, 1698–1706 (1996).
Hutton, M. et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998).
Figlewicz, D. A. et al. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum. Mol. Genet. 3, 1757–1761 (1994).
Gros-Louis, F. et al. A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis. J. Biol. Chem. 279, 45951–45956 (2004).
Pun, S., Santos, A. F., Saxena, S., Xu, L. & Caroni, P. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat. Neurosci. 9, 408–419 (2006).
Fischer, L. R. et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp. Neurol. 185, 232–240 (2004).
Henkel, J. S. et al. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann. Neurol. 55, 221–235 (2004).
Kuhle, J. et al. Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis. Eur. J. Neurol. 16, 771–774 (2009).
Mantovani, S. et al. Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J. Neuroimmunol. 210, 73–79 (2009).
Kipnis, J., Avidan, H., Caspi, R. R. & Schwartz, M. Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: a dialogue with microglia. Proc. Natl Acad. Sci. USA 101 (Suppl. 2), 14663–14669 (2004).
Beers, D. R., Henkel, J. S., Zhao, W., Wang, J. & Appel, S. H. CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc. Natl Acad. Sci. USA 105, 15558–15563 (2008).
Lincecum, J. M. et al. From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis. Nat. Genet. 42, 392–399 (2010).
Ferraiuolo, L. et al. Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS. J. Neurosci. 27, 9201–9219 (2007).
Lobsiger, C. S., Boillee, S. & Cleveland, D. W. Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons. Proc. Natl Acad. Sci. USA 104, 7319–7326 (2007).
Sta, M. et al. Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation. Neurobiol. Dis. 42, 211–220 (2011).
Hensley, K. et al. Primary glia expressing the G93A-SOD1 mutation present a neuroinflammatory phenotype and provide a cellular system for studies of glial inflammation. J. Neuroinflammation 3, 2 (2006).
Di Giorgio, F. P., Boulting, G. L., Bobrowicz, S. & Eggan, K. C. Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 3, 637–648 (2008).
Marchetto, M. C. et al. Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3, 649–657 (2008).
Kaufman, R. J. Orchestrating the unfolded protein response in health and disease. J. Clin. Invest. 110, 1389–1398 (2002).
Yamagishi, S. et al. An in vitro model for Lewy body-like hyaline inclusion/astrocytic hyaline inclusion: induction by ER stress with an ALS-linked SOD1 mutation. PLoS ONE 2, e1030 (2007).
Hitomi, J. et al. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death. J. Cell Biol. 165, 347–356 (2004).
Atkin, J. D. et al. Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J. Biol. Chem. 281, 30152–30165 (2006).
Atkin, J. D. et al. Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis. Neurobiol. Dis. 30, 400–407 (2008).
Saxena, S., Cabuy, E. & Caroni, P. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat. Neurosci. 12, 627–636 (2009).
Vijayalakshmi, K. et al. Evidence of endoplasmic reticular stress in the spinal motor neurons exposed to CSF from sporadic amyotrophic lateral sclerosis patients. Neurobiol. Dis. 41, 695–705 (2011).
Matus, S., Nassif, M., Glimcher, L. H. & Hetz, C. XBP-1 deficiency in the nervous system reveals a homeostatic switch to activate autophagy. Autophagy 5, 1226–1228 (2009).
Hetz, C. et al. XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev. 23, 2294–2306 (2009).
Lev, S., Ben Halevy, D., Peretti, D. & Dahan, N. The VAP protein family: from cellular functions to motor neuron disease. Trends Cell Biol. 18, 282–290 (2008).
Chen, H. J. et al. Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. J. Biol. Chem. 285, 40266–40281 (2010).
Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165 (1995).
Burghes, A. H. & Beattie, C. E. Spinal muscular atrophy: why do low levels of survival motor neuron protein make the motor neurons sick? Nat. Rev. Neurosci. 10, 597–609 (2009).
Mackenzie, I. R., Rademakers, R. & Neumann, M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9, 995–1007 (2010).
Liu-Yesucevitz, L. et al. Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS ONE 5, e13250 (2010).
Ito, D., Seki, M., Tsunoda, Y., Uchiyama, H. & Suzuki, N. Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS. Ann. Neurol. 69, 152–162 (2010).
Dormann, D. et al. ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import. EMBO J. 29, 2841–2857 (2010).
Sephton, C. F. et al. Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes. J. Biol. Chem. 286, 1204–1215 (2011).
Polymenidou, M. et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat. Neurosci. 14, 459–468 (2011).
Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 14, 452–458 (2011).
Xiao, S. et al. RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS. Mol. Cell. Neurosci. 47, 167–180 (2011).
Highley, J. R. et al. TARDBP mutations, amyotrophic lateral sclerosis and alternative splicing in human fibroblasts. Brain Pathol. 20 (Suppl. 1), 32 (2010).
Wegorzewska, I. & Baloh, R. H. TDP-43 based animal models of neurodegeneration: new insights into ALS pathology and pathophysiology. Neurodegen. Dis. 8, 262–274 (2011).
Joyce, P. I., Fratta, P., Fisher, E. M. & Acevedo-Arozena, A. SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments. Mamm. Genome 22, 420–448 (2011).
Greenway, M. J. et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat. Genet. 38, 411–3 (2006).
Kieran, D. et al. Control of motoneuron survival by angiogenin. J. Neurosci. 28, 14056–14061 (2008).
Li, S., Yu, W. & Hu, G. F. Angiogenin inhibits nuclear translocation of apoptosis inducing factor in a Bcl-2-dependent manner. J. Cell Physiol. http://dx.doi.org/10.1002/jcp.22881.
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).
Clement, A. M. et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113–117 (2003).
Boillee, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389–1392 (2006).
Gong, Y. H., Parsadanian, A. S., Andreeva, A., Snider, W. D. & Elliott, J. L. Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J. Neurosci. 20, 660–665 (2000).
Yamanaka, K. et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat. Neurosci. 11, 251–253 (2008).
Nagai, M. et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat. Neurosci. 10, 615–622 (2007).
Pramatarova, A., Laganiere, J., Roussel, J., Brisebois, K. & Rouleau, G. A. Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J. Neurosci. 21, 3369–3374 (2001).
Jaarsma, D., Teuling, E., Haasdijk, E. D., De Zeeuw, C. I. & Hoogenraad, C. C. Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J. Neurosci. 28, 2075–2088 (2008).
Lobsiger, C. S. et al. Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice. Proc. Natl Acad. Sci. USA 106, 4465–4470 (2009).
Turner, B. J., Ackerley, S., Davies, K. E. & Talbot, K. Dismutase-competent SOD1 mutant accumulation in myelinating Schwann cells is not detrimental to normal or transgenic ALS model mice. Hum. Mol. Genet. 19, 815–824 (2010).
Ferraiuolo, L. et al. Dysregulation of astrocyte-motor neuron cross-talk in mutant SOD1 related amyotrophic lateral sclerosis. Brain 134, 2627–2641 (2011).
Shaw, P. J. & Eggett, C. J. Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. J. Neurol. 247 (Suppl. 1), 17–27 (2000).
Durham, H. D. in Motor Neuron Disorders: Blue Books of Practical Neurology (eds Shaw, P. J. & Strong, M. J.) 379–400 (Butterworth-Heinemann, Philadelphia, 2003).
Sullivan, P. G. et al. Intrinsic differences in brain and spinal cord mitochondria: implication for therapeutic interventions. J. Comp. Neurol. 474, 524–534 (2004).
Panov, A. V. et al. Metabolic and functional differences between brain and spinal cord mitochondria underlie different predisposition to pathology. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, R844–R854 (2011).
Vucic, S. & Kiernan, M. C. Axonal excitability properties in amyotrophic lateral sclerosis. Clin. Neurophysiol. 117, 1458–1466 (2006).
Wang, X. & Michaelis, E. K. Selective neuronal vulnerability to oxidative stress in the brain. Front. Aging Neurosci. 2, 12 (2010).
Barber, S. C. et al. Contrasting effects of cerebrospinal fluid from motor neurone disease patients on the survival of primary motor neurons cultured with or without glia. Amyotroph. Lateral Scler. 12, 257–263 (2011).
Dupuis, L., Pradat, P. F., Ludolph, A. C. & Loeffler, J. P. Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurol. 10, 75–82 (2011).
Douville, R. et al. Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann. Neurol. 69, 141–151 (2011).
Orlacchio, A. et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 133, 591–598 (2010).
Luty, A. A. et al. Sigma nonopioid intracellular receptor1 mutations cause fronto-temporal lobar degeneration-motor neuron disease. Ann. Neurol. 68, 639–649 (2010).
Al-Saif, A., Al-Mohanna, F. & Bohlega, S. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann. Neurol. http://dx.doi.org/10.1002/ana.22534.
Mead, R. J. et al. Optimised and rapid pre-clinical screening in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS). PLoS ONE 6, e23244 (2011).
van Zundert, B. et al. Neonatal neuronal circuitry shows hyperexcitable disturbance in a mouse model of the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J. Neurosci. 28, 10864–10874 (2008).
Bories, C. et al. Early electrophysiological abnormalities in lumbar motoneurons in a transgenic mouse model of amyotrophic lateral sclerosis. Eur. J. Neurosci. 25, 451–459 (2008).
Bendotti, C. et al. Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity. J. Neurol. Sci. 191, 25–33 (2001).
Ramesh, T. et al. A genetic model of amyotrophic lateral sclerosis in zebrafish displays phenotypic hallmarks of motoneuron disease. Dis. Model Mech. 3, 652–662 (2010).
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).
Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208–1211 (2009).
Hand, C. K. et al. A novel locus for familial amyotrophic lateral sclerosis on chromosome 18q. Am. J. Hum. Genet. 70, 251–256 (2002).
Sapp, P. C. et al. Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am. J. Hum. Genet. 73, 397–403 (2003).
Renton, A. E. et al. A hexonucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS–FTD. Neuron http://dx.doi.org/10.1016/j.neuron.2011.09.010.
De Jesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron http://dx.doi.org/10.1016/j.neuron.2011.09.011.
The authors gratefully acknowledge financial support provided by the Wellcome Trust, the UK Motor Neurone Disease Association, the Medical Research Council, The Hermann und Lilli Schilling Stiftung, the Deutsche Forschungsgemeinschaft, the European Union under the 7th Framework Programme for RTD—Project MitoTarget (Grant Agreement HEALTH-F2-2008-223388), Project EuroMotor (Grant Agreement FP7/2007-2013 259867), and the ALS Association.
The authors declare no competing financial interests.
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Ferraiuolo, L., Kirby, J., Grierson, A. et al. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol 7, 616–630 (2011). https://doi.org/10.1038/nrneurol.2011.152
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