Skip to main content

Advertisement

Springer Nature Link
Log in

Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson’s disease brain

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Neuronal loss in numerous neurodegenerative disorders has been linked to protein aggregation and oxidative stress. Emerging data regarding overlapping proteinopathy in traditionally distinct neurodegenerative diseases suggest that disease-modifying treatments targeting these pathological features may exhibit efficacy across multiple disorders. Here, we describe proteinopathy distinct from classic synucleinopathy, predominantly comprised of the anti-oxidant enzyme superoxide dismutase-1 (SOD1), in the Parkinson’s disease brain. Significant expression of this pathology closely reflected the regional pattern of neuronal loss. The protein composition and non-amyloid macrostructure of these novel aggregates closely resembles that of neurotoxic SOD1 deposits in SOD1-associated familial amyotrophic lateral sclerosis (fALS). Consistent with the hypothesis that deposition of protein aggregates in neurodegenerative disorders reflects upstream dysfunction, we demonstrated that SOD1 in the Parkinson’s disease brain exhibits evidence of misfolding and metal deficiency, similar to that seen in mutant SOD1 in fALS. Our data suggest common mechanisms of toxic SOD1 aggregation in both disorders and a potential role for SOD1 dysfunction in neuronal loss in the Parkinson’s disease brain. This shared restricted proteinopathy highlights the potential translation of therapeutic approaches targeting SOD1 toxicity, already in clinical trials for ALS, into disease-modifying treatments for Parkinson’s disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Ajroud-Driss S, Siddique T (2015) Sporadic and hereditary amyotrophic lateral sclerosis (ALS). Biochem Biophys Acta 1852:679–684. doi:10.1016/j.bbadis.2014.08.010

    CAS  PubMed  Google Scholar 

  2. Ayers JI, 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. doi:10.1186/2051-5960-2-55

    Article  PubMed  PubMed Central  Google Scholar 

  3. Banci L, Bertini I, Boca M, Calderone V, Cantini F, Girotto S, Vieru M (2009) Structural and dynamic aspects related to oligomerization of apo SOD1 and its mutants. Proc Natl Acad Sci USA 106:6980–6985. doi:10.1073/pnas.0809845106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bandmann O, Davis MB, Marsden CD, Harding AE (1995) Sequence of the superoxide-dismutase 1 (SOD1) gene in familial Parkinson’s disease. J Neurol Neurosurg Psychiatry 59:90–91. doi:10.1136/jnnp.59.1.90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bartnikas TB, Gitlin JD (2003) Mechanisms of biosynthesis of mammalian copper/zinc superoxide dismutase. J Biol Chem 278:33602–33608. doi:10.1074/jbc.M305435200

    Article  CAS  PubMed  Google Scholar 

  6. Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR (2015) Oxidative stress and Parkinson’s disease. Front Neuroanat 9:91. doi:10.3389/fnana.2015.00091

    PubMed  PubMed Central  Google Scholar 

  7. Braak H, Del Tredici K, Rub U, de Vos RAI, Steur E, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211. doi:10.1016/s0197-4580(02)00065-9

    Article  PubMed  Google Scholar 

  8. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134. doi:10.1007/s00441-004-0956-9

    Article  PubMed  Google Scholar 

  9. Breydo L, Wu JW, Uversky VN (2012) Alpha-synuclein misfolding and Parkinson’s disease. Biochem Biophys Acta 1822:261–285. doi:10.1016/j.bbadis.2011.10.002

    CAS  PubMed  Google Scholar 

  10. Brotherton TE, Li Y, Cooper D, Gearing M, Julien JP, Rothstein JD, Boylan K, Glass JD (2012) Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS. Proc Natl Acad Sci USA 109:5505–5510. doi:10.1073/pnas.1115009109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Burrow JN, Blumbergs PC (1992) Substantia nigra degeneration in motor neurone disease: a quantitative study. Aust N Z J Med 22:469–472

    CAS  PubMed  Google Scholar 

  12. Chevreux S, Roudeau S, Fraysse A, Carmona A, Deves G, Solari PL, Mounicou S, Lobinski R, Ortega R (2009) Multimodal analysis of metals in copper-zinc superoxide dismutase isoforms separated on electrophoresis gels. Biochimie 91:1324–1327. doi:10.1016/j.biochi.2009.05.016

    Article  CAS  PubMed  Google Scholar 

  13. Choi J, Rees HD, Weintraub ST, Levey AI, Chin LS, Li L (2005) Oxidative modifications and aggregation of Cu, Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases. J Biol Chem 280:11648–11655. doi:10.1074/jbc.M414327200

    Article  CAS  PubMed  Google Scholar 

  14. Ciryam P, Kundra R, Morimoto RI, Dobson CM, Vendruscolo M (2015) Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases. Trends Pharmacol Sci 36:72–77. doi:10.1016/j.tips.2014.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM (2010) Synergistic interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. JNeurosci 30:7281–7289. doi:10.1523/JNEUROSCI.0490-10.2010

    Article  CAS  Google Scholar 

  16. Da Cruz S, Bui A, Saberi S, Lee SK, Stauffer J, McAlonis-Downes M, Schulte D, Pizzo DP, Parone PA, Cleveland DW et al (2017) Misfolded SOD1 is not a primary component of sporadic ALS. Acta Neuropathologica. doi:10.1007/s00401-017-1688-8

    PubMed Central  Google Scholar 

  17. David DC, Ollikainen N, Trinidad JC, Cary MP, Burlingame AL, Kenyon C (2010) Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol 8:e1000450. doi:10.1371/journal.pbio.1000450

    Article  PubMed  PubMed Central  Google Scholar 

  18. Davies KM, Bohic S, Carmona A, Ortega R, Cottam V, Hare DJ, Finberg JPM, Reyes S, Halliday GM, Mercer JFB et al (2014) Copper pathology in vulnerable brain regions in Parkinson’s disease. Neurobiol Aging 35:858–866. doi:10.1016/j.neurobiolaging.2013.09.034

    Article  CAS  PubMed  Google Scholar 

  19. Dehay B, Bourdenx M, Gorry P, Przedborski S, Vila M, Hunot S, Singleton A, Olanow CW, Merchant KM, Bezard E et al (2015) Targeting alpha-synuclein for treatment of Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol 14:855–866. doi:10.1016/S1474-4422(15)00006-X

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. DelleDonne A, Klos KJ, Fujishiro H, Ahmed Z, Parisi JE, Josephs KA, Frigerio R, Burnett M, Wszolek ZK, Uitti RJ et al (2008) Incidental Lewy body disease and preclinical Parkinson disease. Arch Neurol 65:1074–1080. doi:10.1001/archneur.65.8.1074

    Article  PubMed  Google Scholar 

  21. Deng HX, Shi Y, Furukawa Y, Zhai H, Fu RG, Liu ED, Gorrie GH, Khan MS, Hung WY, Bigio EH et al (2006) Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proc Natl Acad Sci USA 103:7142–7147. doi:10.1073/pnas.0602046103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, Hardy J, Leverenz JB, Del Tredici K, Wszolek ZK et al (2009) Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol 8:1150–1157

    Article  CAS  PubMed  Google Scholar 

  23. Domenico FD, Head E, Butterfield A, Perluigi M (2014) Oxidative Stress and proteostasis network: culprit and casualty of Alzheimer’s-like neurodegeneration. Adv Geriatr 2014:14

    Article  Google Scholar 

  24. Double KL, Reyes S, Werry EL, Halliday GM (2010) Selective cell death in neurodegeneration: why are some neurons spared in vulnerable regions? Prog Neurobiol 92:316–329. doi:10.1016/j.pneurobio.2010.06.001

    Article  CAS  PubMed  Google Scholar 

  25. Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247. doi:10.1038/35041687

    Article  CAS  PubMed  Google Scholar 

  26. 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. doi:10.1074/jbc.M802083200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Guareschi S, Cova E, Cereda C, Ceroni M, Donetti E, Bosco DA, Trotti D, Pasinelli P (2012) An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1. Proc Natl Acad Sci USA 109:5074–5079. doi:10.1073/pnas.1115402109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hare DJ, Double KL (2016) Iron and dopamine: a toxic couple. Brain J Neurol 139:1026–1035. doi:10.1093/brain/aww022

    Article  Google Scholar 

  29. Helferich AM, McLean PJ, Weishaupt JH, Danzer KM (2016) Commentary: alpha-synuclein interacts with SOD1 and promotes its oligomerization. J Neurol Neuromed 1:28–30

    Google Scholar 

  30. Helferich AM, Ruf WP, Grozdanov V, Freischmidt A, Feiler MS, Zondler L, Ludolph AC, McLean PJ, Weishaupt JH, Danzer KM (2015) alpha-synuclein interacts with SOD1 and promotes its oligomerization. Mol Neurodegener 10:66. doi:10.1186/s13024-015-0062-3

    Article  PubMed  PubMed Central  Google Scholar 

  31. Hilton JB, White AR, Crouch PJ (2015) Metal-deficient SOD1 in amyotrophic lateral sclerosis. J Mol Med (Berl) 93:481–487. doi:10.1007/s00109-015-1273-3

    Article  CAS  Google Scholar 

  32. Hung LW, Villemagne VL, Cheng L, Sherratt NA, Ayton S, White AR, Crouch PJ, Lim S, Leong SL, Wilkins S et al (2012) The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson’s disease. J Exp Med 209:837–854. doi:10.1084/jem.20112285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ip P, Mulligan VK, Chakrabartty A (2011) ALS-causing SOD1 mutations promote production of copper-deficient misfolded species. J Mol Biol 409:839–852. doi:10.1016/j.jmb.2011.04.027

    Article  CAS  PubMed  Google Scholar 

  34. Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW (2003) Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol 62:389–397

    Article  CAS  PubMed  Google Scholar 

  35. Kacem I, Funalot B, Torny F, Lautrette G, Andersen PM, Couratier P (2012) Early onset Parkinsonism associated with an intronic SOD1 mutation. Amyotroph Lateral Scler 13:315–317. doi:10.3109/17482968.2011.623301

    Article  CAS  PubMed  Google Scholar 

  36. Kato S, Oda M, Tanabe H (1993) Diminution of dopaminergic neurons in the substantia nigra of sporadic amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol 19:300–304

    Article  CAS  PubMed  Google Scholar 

  37. Kerman A, Liu H-N, Croul S, Bilbao J, Rogaeva E, Zinman L, Robertson J, Chakrabartty A (2010) Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form. Acta Neuropathol 119:335–344. doi:10.1007/s00401-010-0646-5

    Article  PubMed  Google Scholar 

  38. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955. doi:10.1016/S0140-6736(10)61156-7

    Article  CAS  PubMed  Google Scholar 

  39. Koch Y, Helferich AM, Steinacker P, Oeckl P, Walther P, Weishaupt JH, Danzer KM, Otto M (2016) Aggregated alpha-synuclein increases SOD1 oligomerization in a mouse model of amyotrophic lateral sclerosis. Am J Pathol 186:2152–2161. doi:10.1016/j.ajpath.2016.04.008

    Article  CAS  PubMed  Google Scholar 

  40. Li Q, Lau A, Morris TJ, Guo L, Fordyce CB, Stanley EF (2004) A syntaxin 1, Galpha(o), and N-type calcium channel complex at a presynaptic nerve terminal: analysis by quantitative immunocolocalization. J Neurosci 24:4070–4081. doi:10.1523/JNEUROSCI.0346-04.2004

    Article  CAS  PubMed  Google Scholar 

  41. Li W, Ye Y (2008) Polyubiquitin chains: functions, structures, and mechanisms. Cell Mol Life Sci 65:2397–2406. doi:10.1007/s00018-008-8090-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Manno C, Lipari A, Bono V, Taiello AC, La Bella V (2013) Sporadic Parkinson disease and amyotrophic lateral sclerosis complex (Brait–Fahn–Schwartz disease). J Neurol Sci 326:104–106. doi:10.1016/j.jns.2013.01.009

    Article  PubMed  Google Scholar 

  43. Martinez-Lazcano JC, Montes S, Sanchez-Mendoza MA, Rodriguez-Paez L, Perez-Neri I, Boll MC, Campos-Arroyo HD, Rios C, Perez-Severiano F (2014) Sub-chronic copper pretreatment reduces oxidative damage in an experimental Huntington’s disease model. Biol Trace Elem Res 162:211–218. doi:10.1007/s12011-014-0127-0

    Article  CAS  PubMed  Google Scholar 

  44. Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L (2001) beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc Natl Acad Sci USA 98:12245–12250. doi:10.1073/pnas.211412398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mather K, Watts FZ, Carroll M, Whitehead P, Swash M, Cairn N, Burke J (1993) Antibody to an abnormal protein in amyotrophic lateral sclerosis identifies Lewy body-like inclusions in ALS and Lewy bodies in Parkinson’s disease. Neurosci Lett 160:13–16

    Article  CAS  PubMed  Google Scholar 

  46. Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, Andres PL, Mahoney K, Allred P, Alexander K et al (2013) 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. doi:10.1016/S1474-4422(13)70061-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nilsson MR (2004) Techniques to study amyloid fibril formation in vitro. Methods 34:151–160. doi:10.1016/j.ymeth.2004.03.012

    Article  CAS  PubMed  Google Scholar 

  48. Nishiyama K, Murayama S, Shimizu J, Ohya Y, Kwak S, Asayama K, Kanazawa I (1995) Cu/Zn superoxide dismutase-like immunoreactivity is present in Lewy bodies from Parkinson’s disease—a light and electron-microscopic immunocytochemical study. Acta Neuropathol 89:471–474

    Article  CAS  PubMed  Google Scholar 

  49. Opazo CM, Greenough MA, Bush AI (2014) Copper: from neurotransmission to neuroproteostasis. Front Aging Neurosci 6:143. doi:10.3389/fnagi.2014.00143

    Article  PubMed  PubMed Central  Google Scholar 

  50. Orrell RW, King AW, Hilton DA, Campbell MJ, Lane RJ, de Belleroche JS (1995) Familial amyotrophic lateral sclerosis with a point mutation of SOD-1: intrafamilial heterogeneity of disease duration associated with neurofibrillary tangles. J Neurol Neurosurg Psychiatry 59:266–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Petrovic N, Comi A, Ettinger MJ (1996) Identification of an apo-superoxide dismutase (Cu, Zn) pool in human lymphoblasts. J Biol Chem 271:28331–28334

    Article  CAS  PubMed  Google Scholar 

  52. Pickles S, Semmler S, Broom HR, Destroismaisons L, Legroux L, Arbour N, Meiering E, Cashman NR, Vande Velde C (2016) ALS-linked misfolded SOD1 species have divergent impacts on mitochondria. Acta Neuropathol Commun 4:43. doi:10.1186/s40478-016-0313-8

    Article  PubMed  PubMed Central  Google Scholar 

  53. Pratt AJ, Shin DS, Merz GE, Rambo RP, Lancaster WA, Dyer KN, Borbat PP, Poole FL 2nd, Adams MW, Freed JH et al (2014) Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror ALS clinical phenotypes. Proc Natl Acad Sci USA 111:E4568–E4576. doi:10.1073/pnas.1308531111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Roberts BR, Lim NKH, McAllum EJ, Donnelly PS, Hare DJ, Doble PA, Turner BJ, Price KA, Lim SC, Paterson BM et al (2014) Oral treatment with Cu-II(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci 34:8021–8031. doi:10.1523/jneurosci.4196-13.2014

    Article  CAS  PubMed  Google Scholar 

  55. Rotunno MS, Bosco DA (2013) An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis. Front Cell Neurosci 7:253. doi:10.3389/fncel.2013.00253

    Article  PubMed  PubMed Central  Google Scholar 

  56. Roudeau S, Chevreux S, Carmona A, Ortega R (2015) Reduced net charge and heterogeneity of pI isoforms in familial amyotrophic lateral sclerosis mutants of copper/zinc superoxide dismutase. Electrophoresis 36:2482–2488. doi:10.1002/elps.201500187

    Article  CAS  PubMed  Google Scholar 

  57. Saccon RA, Bunton-Stasyshyn RKA, Fisher EMC, Fratta P (2013) Is SOD1 loss of function involved in amyotrophic lateral sclerosis? Brain J Neurol 136:2342–2358. doi:10.1093/brain/awt097

    Article  Google Scholar 

  58. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B et al (2012) Fiji: an open source platform for biological-image analysis. Nat Meth 9:676–682. doi:10.1038/nmeth.2019

    Article  CAS  Google Scholar 

  59. Schneeberger A, Tierney L, Mandler M (2015) Active immunization therapies for Parkinson’s disease and multiple system atrophy. Mov Disord. doi:10.1002/mds.26377

    PubMed  Google Scholar 

  60. Siebert M, Sidransky E, Westbroek W (2014) Glucocerebrosidase is shaking up the synucleinopathies. Brain J Neurol 137:1304–1322. doi:10.1093/brain/awu002

    Article  Google Scholar 

  61. Soon CP, Donnelly PS, Turner BJ, Hung LW, Crouch PJ, Sherratt NA, Tan JL, Lim NK, Lam L, Bica L et al (2011) Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)) protects against peroxynitrite-induced nitrosative damage and prolongs survival in amyotrophic lateral sclerosis mouse model. J Biol Chem 286:44035–44044. doi:10.1074/jbc.M111.274407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 95:6469–6473. doi:10.1073/pnas.95.11.6469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Spillantini MG, Schmidt ML, Lee VMY, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840. doi:10.1038/42166

    Article  CAS  PubMed  Google Scholar 

  64. Takahashi H, Snow BJ, Bhatt MH, Peppard R, Eisen A, Calne DB (1993) Evidence for a dopaminergic deficit in sporadic amyotrophic lateral sclerosis on positron emission scanning. Lancet 342:1016–1018

    Article  CAS  PubMed  Google Scholar 

  65. Toichi K, Yamanaka K, Furukawa Y (2013) Disulfide scrambling describes the oligomer formation of superoxide dismutase (SOD1) proteins in the familial form of amyotrophic lateral sclerosis. J Biol Chem 288:4970–4980. doi:10.1074/jbc.M112.414235

    Article  CAS  PubMed  Google Scholar 

  66. Valdmanis PN, Belzil VV, Lee J, Dion PA, St-Onge J, Hince P, Funalot B, Couratier P, Clavelou P, Camu W et al (2009) A mutation that creates a pseudoexon in SOD1 causes familial ALS. Ann Hum Genet 73:652–657

    Article  CAS  PubMed  Google Scholar 

  67. Volpicelli-Daley LA, Gamble KL, Schultheiss CE, Riddle DM, West AB, Lee VM (2014) Formation of alpha-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes. Mol Biol Cell 25:4010–4023. doi:10.1091/mbc.E14-02-0741

    Article  PubMed  PubMed Central  Google Scholar 

  68. Walker DG, Lue LF, Adler CH, Shill HA, Caviness JN, Sabbagh MN, Akiyama H, Serrano GE, Sue LI, Beach TG et al (2013) Changes in properties of serine 129 phosphorylated alpha-synuclein with progression of Lewy-type histopathology in human brains. Exp Neurol 240:190–204. doi:10.1016/j.expneurol.2012.11.020

    Article  CAS  PubMed  Google Scholar 

  69. Wilcox RR (2012) Introduction to robust estimation and hypothesis testing. Elsevier, Oxford

    Google Scholar 

  70. Williams JR, Trias E, Beilby PR, Lopez NI, Labut EM, Bradford CS, Roberts BR, McAllum EJ, Crouch PJ, Rhoads TW et al (2016) Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD(G93A) mice co-expressing the copper-chaperone-for-SOD. Neurobiol Dis 89:1–9. doi:10.1016/j.nbd.2016.01.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Tissues were received from the New South Wales Tissue Resource Centre at the University of Sydney, supported by the Schizophrenia Research Institute and the National Institute of Alcohol Abuse and Alcoholism [NIH (NIAAA) R24AA012725], from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales, and from The London Neurodegenerative Diseases Brain Bank, which receives funding from the MRC and as part of the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK and Alzheimer’s Society. The authors acknowledge the facilities as well as the scientific and technical assistance of the Australian Microscopy and Microanalysis Research Facility (http://ammrf.org.au) node at the University of Sydney. The authors thank Michael Kuligowski (University of Sydney) for excellent technical assistance, Danielle Davies (Brain and Mind Centre) and Sydney Brain Bank for the antibody provision, and Laura Perrin-Verdugier (University of Bordeaux) for assistance with isoelectric focusing experiments.

Author information

Authors and Affiliations

  1. Discipline of Biomedical Science and Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia

    Benjamin G. Trist, Veronica Cottam, Sian Genoud & Kay L. Double

  2. Neuroscience Research Australia, Sydney, NSW, 2031, Australia

    Katherine M. Davies, Kasun De Silva & Glenda M. Halliday

  3. The University of New South Wales, Sydney, NSW, 2052, Australia

    Katherine M. Davies, Kasun De Silva & Glenda M. Halliday

  4. University of Bordeaux, CENBG, UMR 5797, 33170, Gradignan, France

    Richard Ortega & Stéphane Roudeau

  5. CNRS, IN2P3, CENBG, UMR 5797, 33170, Gradignan, France

    Richard Ortega, Stéphane Roudeau & Asuncion Carmona

  6. Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, The University of New South Wales Australia, Kensington, NSW, 2052, Australia

    Valerie Wasinger

  7. Healthy Brain Ageing Program, University of Sydney, Sydney, NSW, 2006, Australia

    Simon J. G. Lewis

  8. Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia

    Simon J. G. Lewis

  9. The University of New South Wales, Sydney, NSW, 2052, Australia

    Perminder Sachdev

  10. Prince of Wales Hospital, Randwick, NSW, 2031, Australia

    Perminder Sachdev

  11. Maurice Wohl Clinical Neuroscience Institute, King’s College London, Camberwell, London, SE5 9NU, UK

    Bradley Smith, Claire Troakes, Caroline Vance, Christopher Shaw & Safa Al-Sarraj

  12. Biostatistics and Bioinformatics Facility, Bosch Institute, The University of Sydney, Sydney, Australia

    Helen J. Ball

  13. Central Clinical School and Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia

    Glenda M. Halliday

  14. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia

    Dominic J. Hare

  15. Elemental Bio-Imaging Facility, University of Technology Sydney, Broadway, NSW, 2007, Australia

    Dominic J. Hare

Authors
  1. Benjamin G. Trist
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Katherine M. Davies
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Veronica Cottam
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Sian Genoud
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Richard Ortega
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Stéphane Roudeau
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Asuncion Carmona
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Kasun De Silva
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Valerie Wasinger
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Simon J. G. Lewis
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Perminder Sachdev
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Bradley Smith
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Claire Troakes
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Caroline Vance
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Christopher Shaw
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Safa Al-Sarraj
    View author publications

    You can also search for this author inPubMed Google Scholar

  17. Helen J. Ball
    View author publications

    You can also search for this author inPubMed Google Scholar

  18. Glenda M. Halliday
    View author publications

    You can also search for this author inPubMed Google Scholar

  19. Dominic J. Hare
    View author publications

    You can also search for this author inPubMed Google Scholar

  20. Kay L. Double
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

BGT, KMD, DJH, and KLD designed the study. BGT, KMD, and KLD applied for all human tissues. KLD raised funds for the study. BGT and KLD gained human research ethics approval. SJGL, PS, BS, CT, CV, CS, SAS, and GMH provided clinical information for all human tissue cases obtained. BGT, KMD, VC, RO, SR, AC, VW, DJH, and KLD designed and performed the experiments. SG and KDS assisted with the experiments. BGT, KMD, VC, RO, SR, AC, VW, HJB, DJH, and KLD analyzed the data. BGT, DJH, and KLD wrote drafts of the manuscript. All authors edited the manuscript.

Corresponding author

Correspondence to Kay L. Double.

Ethics declarations

Funding

This work was supported by funds from the Australian Research Council, the National Health and Medical Research Council of Australia (NHMRC), Parkinson’s NSW (2015 and 2016 seed grants), and the University of Sydney (Biomedical Science, BRIG).

Conflict of interest

The authors declare no competing financial interests or conflicts of interest.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 4128 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Trist, B.G., Davies, K.M., Cottam, V. et al. Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson’s disease brain. Acta Neuropathol 134, 113–127 (2017). https://doi.org/10.1007/s00401-017-1726-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-017-1726-6

Keywords