Abstract
In many types of familial amyotrophic lateral sclerosis (fALS), mutations cause proteins to gain toxic properties that mediate neurodegenerative processes. It is becoming increasingly clear that the proteins involved in ALS, and those responsible for a host of other neurodegenerative diseases, share many characteristics with a growing number of prion diseases. ALS is a heterogenous disease in which the majority of cases are sporadic in their etiology. Studies investigating the inherited forms of the disease are now beginning to provide evidence that some of this heterogeneity may be due to the existence of distinct conformations that ALS-linked proteins can adopt to produce the equivalent of prion strains. In this review, we discuss the in vitro and in vivo evidence that has been generated to better understand the characteristics of these proteins and how their tertiary structure may impact the disease phenotype.
Similar content being viewed by others
References
Al-Chalabi A, Hardiman O (2013) The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol 9:617–628. https://doi.org/10.1038/nrneurol.2013.203
Alfieri JA, Pino NS, Igaz LM (2014) Reversible behavioral phenotypes in a conditional mouse model of TDP-43 proteinopathies. J Neurosci 34:15244–15259. https://doi.org/10.1523/JNEUROSCI.1918-14.2014
Ash PE, Zhang YJ, Roberts CM, Saldi T, Hutter H, Buratti E et al (2010) Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum Mol Genet 19:3206–3218. https://doi.org/10.1093/hmg/ddq230
Atarashi R, Moore RA, Sim VL, Hughson AG, Dorward DW, Onwubiko HA et al (2007) Ultrasensitive detection of scrapie prion protein using seeded conversion of recombinant prion protein. Nat Methods 4:645–650. https://doi.org/10.1038/nmeth1066
Ayers J, Xu G, Pletnikova O, Troncoso JC, Hart PJ, Borchelt DR (2014) Conformational specificity of the C4F6 SOD1 antibody; low frequency of reactivity in sporadic ALS cases. Acta Neuropathol Commun 2:55. https://doi.org/10.1186/2051-5960-2-55
Ayers JI, Diamond J, Sari A, Fromholt S, Galaleldeen A, Ostrow LW et al (2016) Distinct conformers of transmissible misfolded SOD1 distinguish human SOD1-FALS from other forms of familial and sporadic ALS. Acta Neuropathol 132:827–840. https://doi.org/10.1007/s00401-016-1623-4
Ayers JI, Fromholt S, Koch M, DeBosier A, McMahon B, Xu G et al (2014) Experimental transmissibility of mutant SOD1 motor neuron disease. Acta Neuropathol 128:791–803. https://doi.org/10.1007/s00401-014-1342-7
Ayers JI, Fromholt SE, O'Neal VM, Diamond JH, Borchelt DR (2016) Prion-like propagation of mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical pathways. Acta Neuropathol 131:103–114. https://doi.org/10.1007/s00401-015-1514-0
Ayers JI, Schutt CR, Shikiya RA, Aguzzi A, Kincaid AE, Bartz JC (2011) The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease. PLoS Pathog 7:e1001317. https://doi.org/10.1371/journal.ppat.1001317
Babinchak WM, Haider R, Dumm BK, Sarkar P, Surewicz K, Choi JK et al (2019) The role of liquid-liquid phase separation in aggregation of the TDP-43 low-complexity domain. J Biol Chem 294:6306–6317. https://doi.org/10.1074/jbc.RA118.007222
Banci L, Bertini I, Cantini F, Kozyreva T, Massagni C, Palumaa P et al (2012) Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS). Proc Natl Acad Sci USA 109:13555–13560. https://doi.org/10.1073/pnas.1207493109
Belly A, Moreau-Gachelin F, Sadoul R, Goldberg Y (2005) Delocalization of the multifunctional RNA splicing factor TLS/FUS in hippocampal neurones: exclusion from the nucleus and accumulation in dendritic granules and spine heads. Neurosci Lett 379:152–157. https://doi.org/10.1016/j.neulet.2004.12.071
Bergh J, Zetterstrom P, Andersen PM, Brannstrom T, Graffmo KS, Jonsson PA et al (2015) Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping. Proc Natl Acad Sci USA 112:4489–4494. https://doi.org/10.1073/pnas.1419228112
Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, Caughey B (1995) Non-genetic propagation of strain-specific properties of scrapie prion protein. Nature 375:698–700. https://doi.org/10.1038/375698a0
Bessen RA, Marsh RF (1992) Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol 66:2096–2101
Bessen RA, Marsh RF (1992) Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters. J Gen Virol 73(Pt 2):329–334
Bidhendi EE, Bergh J, Zetterstrom P, Andersen PM, Marklund SL, Brannstrom T (2016) Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease. J Clin Invest 126:2249–2253. https://doi.org/10.1172/JCI84360
Bolton DC, McKinley MP, Prusiner SB (1982) Identification of a protein that purifies with the scrapie prion. Science (New York, NY) 218:1309–1311
Borchelt DR, Lee MK, Slunt HS, Guarnieri M, Xu ZS, Wong PC et al (1994) Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc Natl Acad Sci USA 91:8292–8296
Bosco DA, Morfini G, Karabacak NM, Song Y, Gros-Louis F, Pasinelli P et al (2010) Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci 13:1396–1403. https://doi.org/10.1038/nn.2660
Brotherton TE, Li Y, Cooper D, Gearing M, Julien J-P, Rothstein JD et al (2012) Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1115009109
Bruce M, Chree A, McConnell I, Foster J, Pearson G, Fraser H (1994) Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier. Philos Trans R Soc Lond B Biol Sci 343:405–411. https://doi.org/10.1098/rstb.1994.0036
Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E et al (1998) Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science (New York, NY) 281:1851–1854
Bruns CK, Kopito RR (2007) Impaired post-translational folding of familial ALS-linked Cu, Zn superoxide dismutase mutants. EMBO J 26:855–866. https://doi.org/10.1038/sj.emboj.7601528
Buratti E, Baralle FE (2001) Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J Biol Chem 276:36337–36343. https://doi.org/10.1074/jbc.M104236200
Cao X, Antonyuk SV, Seetharaman SV, Whitson LJ, Taylor AB, Holloway SP et al (2008) Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis. J Biol Chem 283:16169–16177. https://doi.org/10.1074/jbc.M801522200
Chattopadhyay M, Durazo A, Sohn SH, Strong CD, Gralla EB, Whitelegge JP et al (2008) Initiation and elongation in fibrillation of ALS-linked superoxide dismutase. Proc Natl Acad Sci USA 105:18663–18668. https://doi.org/10.1073/pnas.0807058105
Chia R, Tattum MH, Jones S, Collinge J, Fisher EM, Jackson GS (2010) Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis. PLoS ONE 5:e10627. https://doi.org/10.1371/journal.pone.0010627
Chiò A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E et al (2009) Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler 10:310–323. https://doi.org/10.3109/17482960802566824
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913. https://doi.org/10.1038/ncb1901
Collinge J, Sidle KC, Meads J, Ironside J, Hill AF (1996) Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 383:685–690. https://doi.org/10.1038/383685a0
Conicella AE, Zerze GH, Mittal J, Fawzi NL (2016) ALS mutations disrupt phase separation mediated by alpha-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24:1537–1549. https://doi.org/10.1016/j.str.2016.07.007
Crapo JD, Oury T, Rabouille C, Slot JW, Chang LY (1992) Copper, zinc superoxide dismutase is primarily a cytosolic protein in human cells. Proc Natl Acad Sci USA 89:10405–10183
Crown A, McAlary L, Fagerli E, Brown H, Yerbury JJ, Galaleldeen A et al (2020) Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection. PLoS ONE 15:e0227655. https://doi.org/10.1371/journal.pone.0227655
Da Cruz S, Bui A, Saberi S, Lee SK, Stauffer J, McAlonis-Downes M et al (2017) Misfolded SOD1 is not a primary component of sporadic ALS. Acta Neuropathol 134:97–111. https://doi.org/10.1007/s00401-017-1688-8
Dearmond SJ, McKinley MP, Barry RA, Braunfeld MB, McColloch JR, Prusiner SB (1985) Identification of prion amyloid filaments in scrapie-infected brain. Cell 41:221–235
Dearmond SJ, Yang SL, Lee A, Bowler R, Taraboulos A, Groth D et al (1993) Three scrapie prion isolates exhibit different accumulation patterns of the prion protein scrapie isoform. Proc Natl Acad Sci USA 90:6449–6453
DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256. https://doi.org/10.1016/j.neuron.2011.09.011
Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Mistry NA, Vidensky S et al (2013) RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80:415–428. https://doi.org/10.1016/j.neuron.2013.10.015
Ekhtiari Bidhendi E, Bergh J, Zetterstrom P, Forsberg K, Pakkenberg B, Andersen PM, Marklund SL, Brannstrom T (2018) Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis. Acta Neuropathol 136:939–953. https://doi.org/10.1007/s00401-018-1915-y
Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R et al (2018) Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature 561:137–140. https://doi.org/10.1038/s41586-018-0454-y
Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ et al (2018) Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold. Acta Neuropathol 136:699–708. https://doi.org/10.1007/s00401-018-1914-z
Falcon B, Zivanov J, Zhang W, Murzin AG, Garringer HJ, Vidal R et al (2019) Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568:420–423. https://doi.org/10.1038/s41586-019-1026-5
Feiler MS, Strobel B, Freischmidt A, Helferich AM, Kappel J, Brewer BM et al (2015) TDP-43 is intercellularly transmitted across axon terminals. J Cell Biol 211:897–911. https://doi.org/10.1083/jcb.201504057
Feuillette S, Delarue M, Riou G, Gaffuri A-L, Wu J, Lenkei Z et al (2017) Neuron-to-neuron transfer of FUS in Drosophila primary neuronal culture is enhanced by ALS-associated mutations. J Mol Neurosci 62:114–122. https://doi.org/10.1007/s12031-017-0908-y
Field LS, Furukawa Y, O'Halloran TV, Culotta VC (2003) Factors controlling the uptake of yeast copper/zinc superoxide dismutase into mitochondria. J Biol Chem 278:28052–28059. https://doi.org/10.1074/jbc.M304296200
Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ et al (2017) Cryo-EM structures of tau filaments from Alzheimer's disease. Nature 547:185–190. https://doi.org/10.1038/nature23002
Fujii R, Takumi T (2005) TLS facilitates transport of mRNA encoding an actin-stabilizing protein to dendritic spines. J Cell Sci 118:5755–5765. https://doi.org/10.1242/jcs.02692
Furukawa Y, Kaneko K, Watanabe S, Yamanaka K, Nukina N (2011) A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions. J Biol Chem 286:18664–18672. https://doi.org/10.1074/jbc.M111.231209
Furukawa Y, Kaneko K, Yamanaka K, O'Halloran TV, Nukina N (2008) Complete loss of post-translational modifications triggers fibrillar aggregation of SOD1 in the familial form of amyotrophic lateral sclerosis. J Biol Chem 283:24167–24176. https://doi.org/10.1074/jbc.M802083200
Furukawa Y, Torres AS, O'Halloran TV (2004) Oxygen-induced maturation of SOD1: a key role for disulfide formation by the copper chaperone CCS. EMBO J 23:2872–2881. https://doi.org/10.1038/sj.emboj.7600276
Gajdusek DC (1977) Unconventional viruses and the origin and disappearance of kuru. Science (New York, NY) 197:943–960
Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PE, Caulfield T et al (2013) 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. https://doi.org/10.1007/s00401-013-1192-8
Gertz B, Wong M, Martin LJ (2012) Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice. J Neuropathol Exp Neurol 71:162–177. https://doi.org/10.1097/NEN.0b013e318244b635
Giordana MT, Piccinini M, Grifoni S, De Marco G, Vercellino M, Magistrello M et al (2010) TDP-43 redistribution is an early event in sporadic amyotrophic lateral sclerosis. Brain Pathol 20:351–360. https://doi.org/10.1111/j.1750-3639.2009.00284.x
Goedert M, Falcon B, Zhang W, Ghetti B, Scheres SHW (2018) Distinct conformers of assembled tau in Alzheimer's and Pick's diseases. Cold Spring Harb Symp Quant Biol 83:163–171. https://doi.org/10.1101/sqb.2018.83.037580
Goldfarb LG, Petersen RB, Tabaton M, Brown P, LeBlanc AC, Montagna P et al (1992) Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science (New York, NY) 258:806–808
Gonzalez L, Martin S, Jeffrey M (2003) Distinct profiles of PrP(d) immunoreactivity in the brain of scrapie- and BSE-infected sheep: implications for differential cell targeting and PrP processing. J Gen Virol 84:1339–1350. https://doi.org/10.1099/vir.0.18800-0
Grad LI, Guest WC, Yanai A, Pokrishevsky E, O’Neill MA, Gibbs E et al (2011) Intermolecular transmission of superoxide dismutase 1 misfolding in living cells. Proc Natl Acad Sci USA 108:16398–16403. https://doi.org/10.1073/pnas.1102645108
Grad LI, Yerbury JJ, Turner BJ, Guest WC, Pokrishevsky E, O'Neill MA et al (2014) Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc Natl Acad Sci USA 111:3620–3625. https://doi.org/10.1073/pnas.1312245111
Griffith JS (1967) Self-replication and scrapie. Nature 215:1043–1044
Guo W, Chen Y, Zhou X, Kar A, Ray P, Chen X et al (2011) An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat Struct Mol Biol 18:822–830. https://doi.org/10.1038/nsmb.2053
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science (New York, NY) 264:1772–1775
Harrison AF, Shorter J (2017) RNA-binding proteins with prion-like domains in health and disease. Biochem J 474:1417–1438. https://doi.org/10.1042/BCJ20160499
Hasegawa M, Nonaka T, Tsuji H, Tamaoka A, Yamashita M, Kametani F et al (2011) Molecular dissection of TDP-43 proteinopathies. J Mol Neurosci 45:480–485. https://doi.org/10.1007/s12031-011-9571-x
Hayward LJ, Rodriguez JA, Kim JW, Tiwari A, Goto JJ, Cabelli DE et al (2002) Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis. J Biol Chem 277:15923–15931. https://doi.org/10.1074/jbc.M112087200
Hsiao KK, Groth D, Scott M, Yang SL, Serban H, Rapp D et al (1994) Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proc Natl Acad Sci USA 91:9126–9130
Igaz LM, Kwong LK, Lee EB, Chen-Plotkin A, Swanson E, Unger T et al (2011) Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest 121:726–738. https://doi.org/10.1172/JCI44867
Jeffrey M, Martin S, Gonzalez L (2003) Cell-associated variants of disease-specific prion protein immunolabelling are found in different sources of sheep transmissible spongiform encephalopathy. J Gen Virol 84:1033–1045. https://doi.org/10.1099/vir.0.18825-0
Johnson BS, McCaffery JM, Lindquist S, Gitler AD (2008) A yeast TDP-43 proteinopathy model: exploring the molecular determinants of TDP-43 aggregation and cellular toxicity. Proc Natl Acad Sci USA 105:6439–6444. https://doi.org/10.1073/pnas.0802082105
Johnson BS, Snead D, Lee JJ, McCaffery JM, Shorter J, Gitler AD (2009) TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem 284:20329–20339. https://doi.org/10.1074/jbc.M109.010264
Johnston JA, Dalton MJ, Gurney ME, Kopito RR (2000) Formation of high molecular weight complexes of mutant Cu, Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 97:12571–12576. https://doi.org/10.1073/pnas.220417997
Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM et al (2014) TDP-43 is a key player in the clinical features associated with Alzheimer's disease. Acta Neuropathol 127:811–824. https://doi.org/10.1007/s00401-014-1269-z
Jucker M, Walker LC (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501:45–51. https://doi.org/10.1038/nature12481
Kato M, Han TW, Xie S, Shi K, Du X, Wu LC et al (2012) Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149:753–767. https://doi.org/10.1016/j.cell.2012.04.017
Kimberlin RH, Walker C (1977) Characteristics of a short incubation model of scrapie in the golden hamster. J Gen Virol 34:295–304
Kimberlin RH, Walker CA (1978) Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. J Gen Virol 39:487–496
Kocisko DA, Come JH, Priola SA, Chesebro B, Raymond GJ, Lansbury PT et al (1994) Cell-free formation of protease-resistant prion protein. NeuroReport 370:471–474. https://doi.org/10.1038/370471a0
Kovacs GG, Trabattoni G, Hainfellner JA, Ironside JW, Knight RS, Budka H (2002) Mutations of the prion protein gene phenotypic spectrum. J Neurol 249:1567–1582. https://doi.org/10.1007/s00415-002-0896-9
Kraemer BC, Schuck T, Wheeler JM, Robinson LC, Trojanowski JQ, Lee VM et al (2010) Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol 119:409–419. https://doi.org/10.1007/s00401-010-0659-0
Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208. https://doi.org/10.1126/science.1166066
Lee EB, Porta S, Baer GM, Xu Y, Suh E, Kwong LK et al (2017) Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol 134:65–78. https://doi.org/10.1007/s00401-017-1679-9
Leigh PN, Anderton BH, Dodson A, Gallo JM, Swash M, Power DM (1988) Ubiquitin deposits in anterior horn cells in motor neurone disease. Neurosci Lett 93:197–203. https://doi.org/10.1016/0304-3940(88)90081-x
Liebman SW, Chernoff YO (2012) Prions in yeast. Genetics 191:1041–1072. https://doi.org/10.1534/genetics.111.137760
Lowe J, Lennox G, Jefferson D, Morrell K, McQuire D, Gray T et al (1988) A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin. Neurosci Lett 94:203–210. https://doi.org/10.1016/0304-3940(88)90296-0
Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E et al (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113. https://doi.org/10.1007/s00401-011-0845-8
Marsh RF, Kimberlin RH (1975) Comparison of scrapie and transmissible mink encephalopathy in hamsters. II. Clinical signs, pathology, and pathogenesis. J Infect Dis 131:104–110. https://doi.org/10.1093/infdis/131.2.104
McGurk L, Gomes E, Guo L, Shorter J, Bonini NM (2018) Poly(ADP-ribose) engages the TDP-43 nuclear-localization sequence to regulate granulo-filamentous aggregation. Biochemistry 57:6923–6926. https://doi.org/10.1021/acs.biochem.8b00910
McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW et al (2010) TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 69:918–929. https://doi.org/10.1097/NEN.0b013e3181ee7d85
Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E et al (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335–1338. https://doi.org/10.1126/science.1232927
Munch C, O'Brien J, Bertolotti A (2011) Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci USA 108:3548–3553. https://doi.org/10.1073/pnas.1017275108
Nelson PT, Trojanowski JQ, Abner EL, Al-Janabi OM, Jicha GA, Schmitt FA et al (2016) “New Old Pathologies”: AD, PART, and cerebral age-related TDP-43 with sclerosis (CARTS). J Neuropathol Exp Neurol 75:482–498. https://doi.org/10.1093/jnen/nlw033
Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IR (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616. https://doi.org/10.1007/s00401-009-0581-5
Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science (New York, NY) 314:130–133. https://doi.org/10.1126/science.1134108
Niaki AG, Sarkar J, Cai X, Rhine K, Vidaurre V, Guy B et al (2020) Loss of dynamic RNA interaction and aberrant phase separation induced by two distinct types of ALS/FTD-linked FUS mutations. Mol Cell 77(82–94):e84. https://doi.org/10.1016/j.molcel.2019.09.022
Nomura T, Watanabe S, Kaneko K, Yamanaka K, Nukina N, Furukawa Y (2014) Intranuclear aggregation of mutant FUS/TLS as a molecular pathomechanism of amyotrophic lateral sclerosis. J Biol Chem 289:1192–1202. https://doi.org/10.1074/jbc.M113.516492
Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T et al (2013) Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 4:124–134. https://doi.org/10.1016/j.celrep.2013.06.007
Outram GW (1976) The pathogenesis of scrapie in mice. Front Biol 44:325
Pare B, Lehmann M, Beaudin M, Nordstrom U, Saikali S, Julien JP et al (2018) Misfolded SOD1 pathology in sporadic amyotrophic lateral sclerosis. Sci Rep 8:14223. https://doi.org/10.1038/s41598-018-31773-z
Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY et al (2015) A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162:1066–1077. https://doi.org/10.1016/j.cell.2015.07.047
Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M et al (2015) Alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340–344. https://doi.org/10.1038/nature14547
Porta S, Xu Y, Restrepo CR, Kwong LK, Zhang B, Brown HJ et al (2018) Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Nat Commun 9:4220. https://doi.org/10.1038/s41467-018-06548-9
Prudencio M, Hart PJ, Borchelt DR, Andersen PM (2009) Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. Hum Mol Genet 18:3217–3226. https://doi.org/10.1093/hmg/ddp260
Prusiner SB (1978) An approach to the isolation of biological particles using sedimentation analysis. J Biol Chem 253:916–921
Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science (New York, NY) 216:136–144
Prusiner SB, McKinley MP, Bowman KA, Bolton DC, Bendheim PE, Groth DF et al (1983) Scrapie prions aggregate to form amyloid-like birefringent rods. Cell 35:349–358
Ratovitski T, Corson LB, Strain J, Wong P, Cleveland DW, Culotta VC et al (1999) Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds. Hum Mol Genet 8:1451–1460
Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF et al (1996) Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 13:43–47. https://doi.org/10.1038/ng0596-43
Reisin R (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Yearb Neurol Neurosurg 2012:170–172. https://doi.org/10.1016/j.yneu.2012.05.040
Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268. https://doi.org/10.1016/j.neuron.2011.09.010
Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62. https://doi.org/10.1038/362059a0
Saberi S, Stauffer JE, Schulte DJ, Ravits J (2015) Neuropathology of amyotrophic lateral sclerosis and its variants. Neurol Clin 33:855–876. https://doi.org/10.1016/j.ncl.2015.07.012
Saborio GP, Permanne B, Soto C (2001) Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411:810–813. https://doi.org/10.1038/35081095
Sacino AN, Ayers JI, Brooks MM, Chakrabarty P, Hudson VJ 3rd, Howard JK et al (2016) Non-prion-type transmission in A53T alpha-synuclein transgenic mice: a normal component of spinal homogenates from naive non-transgenic mice induces robust alpha-synuclein pathology. Acta Neuropathol 131:151–154. https://doi.org/10.1007/s00401-015-1505-1
Safar J, Wille H, Itri V, Groth D, Serban H, Torchia M et al (1998) Eight prion strains have PrP(Sc) molecules with different conformations. Nat Med 4:1157–1165. https://doi.org/10.1038/2654
Sala FA, Wright GSA, Antonyuk SV, Garratt RC, Hasnain SS (2019) Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS. PLoS Biol 17:e3000141. https://doi.org/10.1371/journal.pbio.3000141
Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A et al (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271–1288. https://doi.org/10.1016/j.neuron.2014.04.047
Sea K, Sohn SH, Durazo A, Sheng Y, Shaw BF, Cao X et al (2015) Insights into the role of the unusual disulfide bond in copper–zinc superoxide dismutase. J Biol Chem 290:2405–2418. https://doi.org/10.1074/jbc.M114.588798
Shaw BF, Valentine JS (2007) How do ALS-associated mutations in superoxide dismutase 1 promote aggregation of the protein? Trends Biochem Sci 32:78–85. https://doi.org/10.1016/j.tibs.2006.12.005
Silverman JM, Fernando SM, Grad LI, Hill AF, Turner BJ, Yerbury JJ et al (2016) Disease mechanisms in ALS: misfolded SOD1 transferred through exosome-dependent and exosome-independent pathways. Cell Mol Neurobiol 36:377–381. https://doi.org/10.1007/s10571-015-0294-3
Smethurst P, Newcombe J, Troakes C, Simone R, Chen YR, Patani R et al (2016) In vitro prion-like behaviour of TDP-43 in ALS. Neurobiol Dis 96:236–247. https://doi.org/10.1016/j.nbd.2016.08.007
Stathopulos PB, Rumfeldt JA, Scholz GA, Irani RA, Frey HE, Hallewell RA et al (2003) Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro. Proc Natl Acad Sci USA 100:7021–7026. https://doi.org/10.1073/pnas.1237797100
Sun Y, Chakrabartty A (2017) Phase to phase with TDP-43. Biochemistry 56:809–823. https://doi.org/10.1021/acs.biochem.6b01088
Tatom JB, Wang DB, Dayton RD, Skalli O, Hutton ML, Dickson DW et al (2009) Mimicking aspects of frontotemporal lobar degeneration and Lou Gehrig's disease in rats via TDP-43 overexpression. Mol Ther 17:607–613. https://doi.org/10.1038/mt.2009.3
Telling GC, Parchi P, Dearmond SJ, Cortelli P, Montagna P, Gabizon R et al (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science (New York, NY) 274:2079–2082
Tokuda E, Takei YI, Ohara S, Fujiwara N, Hozumi I, Furukawa Y (2019) Wild-type Cu/Zn-superoxide dismutase is misfolded in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis. Mol Neurodegener 14:42. https://doi.org/10.1186/s13024-019-0341-5
Tsao W, Jeong YH, Lin S, Ling J, Price DL, Chiang PM et al (2012) Rodent models of TDP-43: recent advances. Brain Res 1462:26–39. https://doi.org/10.1016/j.brainres.2012.04.031
Valentine JS, Doucette PA, Potter SZ (2005) Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis. Annu Rev Biochem 74:563–593. https://doi.org/10.1146/annurev.biochem.72.121801.161647
Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science (New York, NY) 323:1208–1211. https://doi.org/10.1126/science.1165942
Voigt A, Herholz D, Fiesel FC, Kaur K, Muller D, Karsten P et al (2010) TDP-43-mediated neuron loss in vivo requires RNA-binding activity. PLoS ONE 5:e12247. https://doi.org/10.1371/journal.pone.0012247
Wang J, Farr GW, Zeiss CJ, Rodriguez-Gil DJ, Wilson JH, Furtak K et al (2009) Progressive aggregation despite chaperone associations of a mutant SOD1-YFP in transgenic mice that develop ALS. Proc Natl Acad Sci USA 106:1392–1397. https://doi.org/10.1073/pnas.0813045106
Wang J, Slunt H, Gonzales V, Fromholt D, Coonfield M, Copeland NG et al (2003) Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature. Hum Mol Genet 12:2753–2764. https://doi.org/10.1093/hmg/ddg312
Wang J, Xu G, Borchelt DR (2002) High molecular weight complexes of mutant superoxide dismutase 1: age-dependent and tissue-specific accumulation. Neurobiol Dis 9:139–148. https://doi.org/10.1006/nbdi.2001.0471
Wang J, Xu G, Slunt HH, Gonzales V, Coonfield M, Fromholt D et al (2005) Coincident thresholds of mutant protein for paralytic disease and protein aggregation caused by restrictively expressed superoxide dismutase cDNA. Neurobiol Dis 20:943–952. https://doi.org/10.1016/j.nbd.2005.06.005
Wang WY, Pan L, Su SC, Quinn EJ, Sasaki M, Jimenez JC et al (2013) Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat Neurosci 16:1383–1391. https://doi.org/10.1038/nn.3514
Watts JC, Giles K, Oehler A, Middleton L, Dexter DT, Gentleman SM et al (2013) Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci USA 110:19555–19560. https://doi.org/10.1073/pnas.1318268110
Westergard T, Jensen BK, Wen X, Cai J, Kropf E, Iacovitti L et al (2016) Cell-to-cell transmission of dipeptide repeat proteins linked to C9orf72-ALS/FTD. Cell Rep 17:645–652. https://doi.org/10.1016/j.celrep.2016.09.032
Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I et al (2010) 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. https://doi.org/10.1073/pnas.0912417107
Zhang W, Tarutani A, Newell KL, Murzin AG, Matsubara T, Falcon B et al (2020) Novel tau filament fold in corticobasal degeneration. Nature. https://doi.org/10.1038/s41586-020-2043-0
Zhang YJ, Xu YF, Cook C, Gendron TF, Roettges P, Link CD et al (2009) Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci USA 106:7607–7612. https://doi.org/10.1073/pnas.0900688106
Zhang YJ, Xu YF, Dickey CA, Buratti E, Baralle F, Bailey R et al (2007) Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. J Neurosci 27:10530–10534. https://doi.org/10.1523/JNEUROSCI.3421-07.2007
Zu T, Liu Y, Banez-Coronel M, Reid T, Pletnikova O, Lewis J et al (2013) RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci USA 110:E4968–4977. https://doi.org/10.1073/pnas.1315438110
Acknowledgements
This work was supported by a grant from the National Institutes of Neurological Disease and Stroke (1R01NA092788-01).
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Ayers, J.I., Borchelt, D.R. Phenotypic diversity in ALS and the role of poly-conformational protein misfolding. Acta Neuropathol 142, 41–55 (2021). https://doi.org/10.1007/s00401-020-02222-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-020-02222-x