Animal models of adult-onset neurodegenerative diseases have enhanced the understanding of the molecular pathogenesis of Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Nevertheless, our understanding of these disorders and the development of mechanistically designed therapeutics can still benefit from more rigorous use of the models and from generation of animals that more faithfully recapitulate human disease. Here we review the current state of rodent models for Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. We discuss the limitations and utility of current models, issues regarding translatability, and future directions for developing animal models of these human disorders.
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Liu, C., Oikonomopoulos, A., Sayed, N. & Wu, J. C. Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. Development 145, dev156166 (2018).
Holtzman, D. M., Morris, J. C. & Goate, A. M. Alzheimer’s disease: the challenge of the second century. Sci. Transl. Med. 3, 77sr1 (2011).
Jack, C. R. Jr. et al. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 87, 539–547 (2016).
Holtzman, D. M. et al. Tau: From research to clinical development. Alzheimers Dement. 12, (1033–1039 (2016).
Carmona, S., Hardy, J. & Guerreiro, R. The genetic landscape of Alzheimer disease. Handb. Clin. Neurol. 148, 395–408 (2018).
Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013).
Tansey, K. E., Cameron, D. & Hill, M. J. Genetic risk for Alzheimer’s disease is concentrated in specific macrophage and microglial transcriptional networks. Genome Med. 10, 14 (2018).
Ashe, K. H. & Zahs, K. R. Probing the biology of Alzheimer’s disease in mice. Neuron 66, 631–645 (2010).
LaFerla, F. M. & Green, K. N. Animal models of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006320 (2012).
Price, D. L., Tanzi, R. E., Borchelt, D. R. & Sisodia, S. S. Alzheimer’s disease: genetic studies and transgenic models. Annu. Rev. Genet. 32, 461–493 (1998).
Sasaguri, H. et al. APP mouse models for Alzheimer’s disease preclinical studies. EMBO J. 36, 2473–2487 (2017).
Golde, T. E., Schneider, L. S. & Koo, E. H. Anti-aβ therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron 69, 203–213 (2011).
Haass, C. & De Strooper, B. The presenilins in Alzheimer’s disease–proteolysis holds the key. Science 286, 916–919 (1999).
Spires, T. L. & Hyman, B. T. Neuronal structure is altered by amyloid plaques. Rev. Neurosci. 15, 267–278 (2004).
Kim, J. et al. Normal cognition in transgenic BRI2-Aβ mice. Mol. Neurodegener. 8, 15 (2013).
McGowan, E. et al. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47, 191–199 (2005).
Saito, T. et al. Single App knock-in mouse models of Alzheimer’s disease. Nat. Neurosci. 17, 661–663 (2014).
Goedert, M., Eisenberg, D. S. & Crowther, R. A. Propagation of tau aggregates and neurodegeneration. Annu. Rev. Neurosci. 40, 189–210 (2017).
McGowan, E., Eriksen, J. & Hutton, M. A decade of modeling Alzheimer’s disease in transgenic mice. Trends Genet. 22, 281–289 (2006).
Strang, K. H. et al. Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies. J. Biol. Chem. 293, 2408–2421 (2018).
Andorfer, C. et al. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J. Neurosci. 25, 5446–5454 (2005).
Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402–405 (2000).
de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73, 685–697 (2012).
Fu, H. et al. Tau pathology induces excitatory neuron loss, grid cell dysfunction, and spatial memory deficits reminiscent of early Alzheimer’s disease. Neuron 93, 533–541.e5 (2017).
Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005).
Bolmont, T. et al. Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. Am. J. Pathol. 171, 2012–2020 (2007).
Götz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491–1495 (2001).
Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).
Oddo, S. et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39, 409–421 (2003).
Savitt, J. M., Dawson, V. L. & Dawson, T. M. Diagnosis and treatment of Parkinson disease: molecules to medicine. J. Clin. Invest. 116, 1744–1754 (2006).
Spillantini, M. G. et al. Alpha-synuclein in Lewy bodies. Nature 388, 839–840 (1997).
Klein, C. & Westenberger, A. Genetics of Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2, a008888 (2012).
Martin, I., Dawson, V. L. & Dawson, T. M. Recent advances in the genetics of Parkinson’s disease. Annu. Rev. Genomics Hum. Genet. 12, 301–325 (2011).
Scott, L., Dawson, V. L. & Dawson, T. M. Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson’s disease genes. Exp. Neurol. 298(Pt B.), 191–201 (2017).
Chang, D. et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat. Genet. 49, 1511–1516 (2017).
Braak, H. & Del Tredici, K. Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff. J. Parkinsons Dis. 7(s1.), S71–S85 (2017).
Carlsson, A., Lindqvist, M. & Magnusson, T. 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180, 1200 (1957).
Lees, A. J., Tolosa, E. & Olanow, C. W. Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr. Mov. Disord. 30, 19–36 (2015).
Vingill, S., Connor-Robson, N. & Wade-Martins, R. Are rodent models of Parkinson’s disease behaving as they should? Behav. Brain Res. 352, 133–141 (2018).
Blesa, J. & Przedborski, S. Parkinson’s disease: animal models and dopaminergic cell vulnerability. Front. Neuroanat. 8, 155 (2014).
Athauda, D. & Foltynie, T. Challenges in detecting disease modification in Parkinson’s disease clinical trials. Parkinsonism Relat. Disord. 32, 1–11 (2016).
Olanow, C. W., Kieburtz, K. & Katz, R. Clinical approaches to the development of a neuroprotective therapy for PD. Exp. Neurol. 298(Pt B.), 246–251 (2017).
Koprich, J. B., Kalia, L. V. & Brotchie, J. M. Animal models of α-synucleinopathy for Parkinson disease drug development. Nat. Rev. Neurosci. 18, 515–529 (2017).
Visanji, N. P. et al. α-Synuclein-based animal models of Parkinson’s disease: challenges and opportunities in a new era. Trends Neurosci. 39, 750–762 (2016).
Hatami, A. & Chesselet, M. F. Transgenic rodent models to study alpha-synuclein pathogenesis, with a focus on cognitive deficits. Curr. Top. Behav. Neurosci. 22, 303–330 (2015).
Bezard, E., Yue, Z., Kirik, D. & Spillantini, M. G. Animal models of Parkinson’s disease: limits and relevance to neuroprotection studies. Mov. Disord. 28, 61–70 (2013).
Dawson, T. M., Ko, H. S. & Dawson, V. L. Genetic animal models of Parkinson’s disease. Neuron 66, 646–661 (2010).
McDowell, K. & Chesselet, M. F. Animal models of the non-motor features of Parkinson’s disease. Neurobiol. Dis. 46, 597–606 (2012).
Xiong, Y., Dawson, T. M. & Dawson, V. L. Models of LRRK2-associated Parkinson’s disease. Adv. Neurobiol. 14, 163–191 (2017).
Lin, X. et al. Conditional expression of Parkinson’s disease-related mutant α-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1. J. Neurosci. 32, 9248–9264 (2012).
Daniel, G. & Moore, D. J. Modeling LRRK2 pathobiology in Parkinson’s disease: from yeast to rodents. Curr. Top. Behav. Neurosci. 22, 331–368 (2015).
Van der Perren, A., Van den Haute, C. & Baekelandt, V. Viral vector-based models of Parkinson’s disease. Curr. Top. Behav. Neurosci. 22, 271–301 (2015).
Tofaris, G. K. et al. Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders. J. Neurosci. 26, 3942–3950 (2006).
Volta, M. & Melrose, H. LRRK2 mouse models: dissecting the behavior, striatal neurochemistry and neurophysiology of PD pathogenesis. Biochem. Soc. Trans. 45, 113–122 (2017).
Sloan, M., Alegre-Abarrategui, J. & Wade-Martins, R. Insights into LRRK2 function and dysfunction from transgenic and knockout rodent models. Biochem. Soc. Trans. 40, 1080–1085 (2012).
Lee, Y., Dawson, V. L. & Dawson, T. M. Animal models of Parkinson’s disease: vertebrate genetics. Cold Spring Harb. Perspect. Med. 2, a009324 (2012).
Lee, B. D. et al. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease. Nat. Med. 16, 998–1000 (2010).
Tsika, E. et al. Adenoviral-mediated expression of G2019S LRRK2 induces striatal pathology in a kinase-dependent manner in a rat model of Parkinson’s disease. Neurobiol. Dis. 77, 49–61 (2015).
Xiong, Y. et al. Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice. Proc. Natl. Acad. Sci. USA 115, 1635–1640 (2018).
Giaime, E. et al. Age-dependent dopaminergic neurodegeneration and impairment of the autophagy-lysosomal pathway in LRRK-deficient mice. Neuron 96, 796–807.e6 (2017).
Moehle, M. S. et al. LRRK2 inhibition attenuates microglial inflammatory responses. J. Neurosci. 32, 1602–1611 (2012).
Yun, S. P. et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. 24, 931–938 (2018).
Lee, Y. et al. PINK1 primes parkin-mediated ubiquitination of PARIS in dopaminergic neuronal survival. Cell Rep. 18, 918–932 (2017).
Shin, J. H. et al. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease. Cell 144, 689–702 (2011).
Kitada, T., Tong, Y., Gautier, C. A. & Shen, J. Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. J. Neurochem. 111, 696–702 (2009).
Low, B. E., Kutny, P. M. & Wiles, M. V. Simple, efficient CRISPR-Cas9-mediated gene editing in mice: strategies and methods. Methods Mol. Biol. 1438, 19–53 (2016).
Lee, Y. et al. Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat. Neurosci. 16, 1392–1400 (2013).
Lu, X. H. et al. Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein. J. Neurosci. 29, 1962–1976 (2009).
Andersen, P. M. & Al-Chalabi, A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat. Rev. Neurol. 7, 603–615 (2011).
Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
Lagier-Tourenne, C., Polymenidou, M. & Cleveland, D. W. TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum. Mol. Genet. 19(R1), R46–R64 (2010).
Taylor, J. P., Brown, R. H. Jr. & Cleveland, D. W. Decoding ALS: from genes to mechanism. Nature 539, 197–206 (2016).
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).
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).
Hutton, M., Lewis, J., Dickson, D., Yen, S. H. & McGowan, E. Analysis of tauopathies with transgenic mice. Trends Mol. Med. 7, 467–470 (2001).
Ittner, L. M. et al. FTD and ALS–translating mouse studies into clinical trials. Nat. Rev. Neurol. 11, 360–366 (2015).
Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994).
Philips, T. & Rothstein, J. D. Rodent models of amyotrophic lateral sclerosis. Curr. Protocols Pharmacol. 69, 1–21 (2015).
Boillée, S., Vande Velde, C. & Cleveland, D. W. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52, 39–59 (2006).
Reaume, A. G. et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat. Genet. 13, 43–47 (1996).
Ilieva, H., Polymenidou, M. & Cleveland, D. W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761–772 (2009).
Wu, L. S. et al. TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis 48, 56–62 (2010).
Sephton, C. F. et al. TDP-43 is a developmentally regulated protein essential for early embryonic development. J. Biol. Chem. 285, 6826–6834 (2010).
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).
Picher-Martel, V., Valdmanis, P. N., Gould, P. V., Julien, J. P. & Dupré, N. From animal models to human disease: a genetic approach for personalized medicine in ALS. Acta Neuropathol. Commun. 4, 70 (2016).
Swarup, V. et al. Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments. Brain 134, 2610–2626 (2011).
Arnold, E. S. et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc. Natl. Acad. Sci. USA 110, E736–E745 (2013).
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).
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).
Spiller, K. J. et al. Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nat. Neurosci. 21, 329–340 (2018).
Nolan, M., Talbot, K. & Ansorge, O. Pathogenesis of FUS-associated ALS and FTD: insights from rodent models. Acta Neuropathol. Commun. 4, 99 (2016).
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).
Devoy, A. et al. Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in ‘FUSDelta14’ knockin mice. Brain 140, 2797–2805 (2017).
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).
Fil, D. et al. Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease. Hum. Mol. Genet. 26, 686–701 (2017).
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).
Wen, X., Westergard, T., Pasinelli, P. & Trotti, D. Pathogenic determinants and mechanisms of ALS/FTD linked to hexanucleotide repeat expansions in the C9orf72 gene. Neurosci. Lett. 636, 16–26 (2017).
Shi, Y. et al. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat. Med. 24, 313–325 (2018).
O’Rourke, J. G. et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329 (2016).
Burberry, A. et al. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci. Transl. Med. 8, 347ra93 (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).
Chew, J. et al. Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348, 1151–1154 (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).
O’Rourke, J. G. et al. C9orf72 BAC transgenic mice display typical pathologic features of ALS/FTD. Neuron 88, 892–901 (2015).
Liu, Y. et al. C9orf72 BAC mouse model with motor deficits and neurodegenerative features of ALS/FTD. Neuron 90, 521–534 (2016).
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).
Zhang, Y. J. et al. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat. Neurosci. 19, 668–677 (2016).
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).
Prusiner, S. B. Prions. Proc. Natl. Acad. Sci. USA 95, 13363–13383 (1998).
Guo, J. L. & Lee, V. M. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat. Med. 20, 130–138 (2014).
Stopschinski, B. E. & Diamond, M. I. The prion model for progression and diversity of neurodegenerative diseases. Lancet Neurol. 16, 323–332 (2017).
Walker, L. C., Diamond, M. I., Duff, K. E. & Hyman, B. T. Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol. 70, 304–310 (2013).
Walker, L. C. & Jucker, M. Neurodegenerative diseases: expanding the prion concept. Annu. Rev. Neurosci. 38, 87–103 (2015).
Bilen, J. & Bonini, N. M. Drosophila as a model for human neurodegenerative disease. Annu. Rev. Genet. 39, 153–171 (2005).
Li, J. & Le, W. Modeling neurodegenerative diseases in Caenorhabditis elegans. Exp. Neurol. 250, 94–103 (2013).
Link, C. D. Invertebrate models of Alzheimer’s disease. Genes Brain Behav. 4, 147–156 (2005).
Muqit, M. M. & Feany, M. B. Modelling neurodegenerative diseases in Drosophila: a fruitful approach? Nat. Rev. Neurosci. 3, 237–243 (2002).
Prüßing, K., Voigt, A. & Schulz, J. B. Drosophila melanogaster as a model organism for Alzheimer’s disease. Mol. Neurodegener. 8, 35 (2013).
Winderickx, J. et al. Protein folding diseases and neurodegeneration: lessons learned from yeast. Biochim. Biophys. Acta 1783, 1381–1395 (2008).
Heuer, E., Rosen, R. F., Cintron, A. & Walker, L. C. Nonhuman primate models of Alzheimer-like cerebral proteopathy. Curr. Pharm. Des. 18, 1159–1169 (2012).
Berry, J. D., Cudkowicz, M. E. & Shefner, J. M. Predicting success: optimizing phase II ALS trials for the transition to phase III. Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 1–8 (2014).
Bateman, R. J. et al. The DIAN-TU next generation Alzheimer’s prevention trial: adaptive design and disease progression model. Alzheimers Dement. 13, 8–19 (2017).
Reiman, E. M., Langbaum, J. B. & Tariot, P. N. Alzheimer’s prevention initiative: a proposal to evaluate presymptomatic treatments as quickly as possible. Biomark. Med. 4, 3–14 (2010).
Sperling, R. A. et al. The A4 study: stopping AD before symptoms begin? Sci. Transl. Med. 6, 228fs13 (2014).
Scott, S. et al. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph. Lateral Scler. 9, 4–15 (2008).
Ludolph, A. C. et al. Guidelines for preclinical animal research in ALS/MND: A consensus meeting. Amyotroph. Lateral Scler. 11, 38–45 (2010).
Gurney, M. E. et al. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann. Neurol. 39, 147–157 (1996).
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).
Miller, T. M. et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 12, 435–442 (2013).
Nicholson, K. A., Cudkowicz, M. E. & Berry, J. D. Clinical trial designs in amyotrophic lateral sclerosis: does one design fit all? Neurotherapeutics 12, 376–383 (2015).
Breschi, A., Gingeras, T. R. & Guigó, R. Comparative transcriptomics in human and mouse. Nat. Rev. Genet. 18, 425–440 (2017).
Ahmed, R. M. et al. Mouse models of frontotemporal dementia: A comparison of phenotypes with clinical symptomatology. Neurosci. Biobehav. Rev. 74(Pt A), 126–138 (2017).
Lutz, C. Mouse models of ALS: Past, present and future. Brain Res. 1693(Pt A), 1–10 (2018).
Onos, K. D., Sukoff Rizzo, S. J., Howell, G. R. & Sasner, M. Toward more predictive genetic mouse models of Alzheimer’s disease. Brain Res. Bull. 122, 1–11 (2016).
Liu, E. T. et al. Of mice and CRISPR: The post-CRISPR future of the mouse as a model system for the human condition. EMBO Rep. 18, 187–193 (2017).
He, Z. et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29–38 (2018).
Eisele, Y. S. et al. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 330, 980–982 (2010).
Kaufman, S. K. et al. Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 92, 796–812 (2016).
Watts, J. C. et al. Serial propagation of distinct strains of Aβ prions from Alzheimer’s disease patients. Proc. Natl. Acad. Sci. USA 111, 10323–10328 (2014).
Brettschneider, J., Del Tredici, K., Lee, V. M. & Trojanowski, J. Q. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat. Rev. Neurosci. 16, 109–120 (2015).
Lee, S. J., Desplats, P., Sigurdson, C., Tsigelny, I. & Masliah, E. Cell-to-cell transmission of non-prion protein aggregates. Nat. Rev. Neurol. 6, 702–706 (2010).
Brundin, P., Melki, R. & Kopito, R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat. Rev. Mol. Cell Biol. 11, 301–307 (2010).
Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).
Irwin, D. J. et al. Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 70, 462–468 (2013).
Collinge, J. Mammalian prions and their wider relevance in neurodegenerative diseases. Nature 539, 217–226 (2016).
Golde, T. E., Borchelt, D. R., Giasson, B. I. & Lewis, J. Thinking laterally about neurodegenerative proteinopathies. J. Clin. Invest. 123, 1847–1855 (2013).
Sacino, A. N. et al. Non-prion-type transmission in A53T α-synuclein transgenic mice: a normal component of spinal homogenates from naïve non-transgenic mice induces robust α-synuclein pathology. Acta Neuropathol. 131, 151–154 (2016).
Greenland, S. et al. Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations. Eur. J. Epidemiol. 31, 337–350 (2016).
This work was supported by grants from the NIH/NINDS NS38377 Morris K. Udall Parkinson’s Disease Research Center, NIH/NINDS NS082205, NIH/NINDS NS098006, the JPB Foundation and Michael J. Fox Foundation. T.M.D. is supported by the Abramson Professorship. T.M.D. acknowledges joint participation by the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital, the Johns Hopkins University School of Medicine, and the Foundation’s Parkinson’s Disease Program M-1, M-2, M-2015. Supported by grants from the NIH to T.E.G. (P01CA166009, U01AG046139 R01AG018454, P50AG047266) and to C.L.T. (R01NS087227). C.L.-T. was supported by grants from the ALS Association, the Target ALS Foundation, ALS Finding a Cure, the Association Française contre les Myopathies, and the Pape Adams Charitable Foundation.
T.E.G. is a cofounder of Lacerta Inc. T.M.D. is a consultant and advisor to Sun Pharma Advanced Research Company Ltd. T.M.D. is a member of American Gene Technologies International Inc., advisory board and owns stock options in the company. T.M.D. is a consultant to Inhibikase Therapeutics and owns stock options in the company. T.M.D. is a founder of Valted, LLC and holds an ownership equity interest in the company. T.M.D. is an inventor of technology of Neuraly, Inc. that has optioned from Johns Hopkins University. T.M.D. is a founder of, and holds shares of stock options as well as equity in, Neuraly, Inc. All these arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies.
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Dawson, T.M., Golde, T.E. & Lagier-Tourenne, C. Animal models of neurodegenerative diseases. Nat Neurosci 21, 1370–1379 (2018). https://doi.org/10.1038/s41593-018-0236-8
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