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Open Access 01-12-2015 | Research article

Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation

Authors: Aoife P. Kiely, Helen Ling, Yasmine T. Asi, Eleanna Kara, Christos Proukakis, Anthony H. Schapira, Huw R. Morris, Helen C. Roberts, Steven Lubbe, Patricia Limousin, Patrick A. Lewis, Andrew J. Lees, Niall Quinn, John Hardy, Seth Love, Tamas Revesz, Henry Houlden, Janice L. Holton

Published in: Molecular Neurodegeneration | Issue 1/2015

Abstract

Background

We and others have described the neurodegenerative disorder caused by G51D SNCA mutation which shares characteristics of Parkinson’s disease (PD) and multiple system atrophy (MSA). The objective of this investigation was to extend the description of the clinical and neuropathological hallmarks of G51D mutant SNCA-associated disease by the study of two additional cases from a further G51D SNCA kindred and to compare the features of this group with a SNCA duplication case and a H50Q SNCA mutation case.

Results

All three G51D patients were clinically characterised by parkinsonism, dementia, visual hallucinations, autonomic dysfunction and pyramidal signs with variable age at disease onset and levodopa response. The H50Q SNCA mutation case had a clinical picture that mimicked late-onset idiopathic PD with a good and sustained levodopa response. The SNCA duplication case presented with a clinical phenotype of frontotemporal dementia with marked behavioural changes, pyramidal signs, postural hypotension and transiently levodopa responsive parkinsonism. Detailed post-mortem neuropathological analysis was performed in all cases. All three G51D cases had abundant α-synuclein pathology with characteristics of both PD and MSA. These included widespread cortical and subcortical neuronal α-synuclein inclusions together with small numbers of inclusions resembling glial cytoplasmic inclusions (GCIs) in oligodendrocytes. In contrast the H50Q and SNCA duplication cases, had α-synuclein pathology resembling idiopathic PD without GCIs. Phosphorylated α-synuclein was present in all inclusions types in G51D cases but was more restricted in SNCA duplication and H50Q mutation. Inclusions were also immunoreactive for the 5G4 antibody indicating their highly aggregated and likely fibrillar state.

Conclusions

Our characterisation of the clinical and neuropathological features of the present small series of G51D SNCA mutation cases should aid the recognition of this clinico-pathological entity. The neuropathological features of these cases consistently share characteristics of PD and MSA and are distinct from PD patients carrying the H50Q or SNCA duplication.

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Lashuel HA, Overk CR, Oueslati A, Masliah E. The many faces of [alpha]-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013;14(1):38–48.PubMedCentralCrossRefPubMed

Polymeropoulos M, Lavedan C, Leroy E, Ide S, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–7.CrossRefPubMed

Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, et al. The new mutation, E46K, of α-synuclein causes parkinson and Lewy body dementia. Ann Neurol. 2004;55(2):164–73.CrossRefPubMed

Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet. 1998;18:106–8.CrossRefPubMed

Proukakis C, Dudzik CG, Breier T, MacKay DS, Cooper JM, Millhauser GL, et al. A novel alpha-synuclein missense mutation in Parkinson’s disease. Neurology. 2012;80(11):1062–4.CrossRef

Kiely AP, Asi Y, Kara E, Limousin P, Ling H, Lewis P, et al. α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy? Acta Neuropathol. 2013;125(5):753–69.PubMedCentralCrossRefPubMed

Pasanen P, Myllykangas L, Siitonen M, Raunio A, Kaakkola S, Lyytinen J, et al. A novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson’s disease-type pathology. Neurobiol Aging. 2014.

Kara E, Lewis PA, Ling H, Proukakis C, Houlden H, Hardy J. α-Synuclein mutations cluster around a putative protein loop. Neurosci Lett. 2013;546:67–70.PubMedCentralCrossRefPubMed

Collaboration TM-SAR. Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med. 2013;369:233–44.CrossRef

10.

Lesage S, Anheim M, Letournel F, Bousset L, Honoré A, Rozas N, et al. G51D α-synuclein mutation causes a novel Parkinsonian–pyramidal syndrome. Ann Neurol. 2013;73(4):459–71.CrossRefPubMed

11.

Tokutake T, Ishikawa A, Yoshimura N, Miyashita A, Kuwano R, Nishizawa M, et al. Clinical and neuroimaging features of patient with early-onset Parkinson’s disease with dementia carrying SNCA p.G51D mutation. Parkinsonism Relat Disord. 2014;20(2):262–4.CrossRefPubMed

12.

Kara E, Kiely AP, Proukakis C, Giffin N, Love S, Hehir J, et al. A 6.4 mb duplication of the α-synuclein locus causing frontotemporal dementia and parkinsonism: phenotype-genotype correlations. JAMA Neurol. 2014;71(9):1162–71.PubMedCentralCrossRefPubMed

13.

Seidel K, Mahlke J, Siswanto S, Krüger R, Heinsen H, Auburger G, et al. The brainstem pathologies of Parkinson’s disease and dementia with lewy bodies. Brain Pathol. 2014;25(2):121–35.CrossRefPubMed

14.

Kovacs G, Wagner U, Dumont B, Pikkarainen M, Osman A, Streichenberger N, et al. An antibody with high reactivity for disease-associated α-synuclein reveals extensive brain pathology. Acta Neuropathol. 2012;124(1):37–50.CrossRefPubMed

15.

Kovacs GG, Breydo L, Green R, Kis V, Puska G, Lőrincz P, et al. Intracellular processing of disease-associated α-synuclein in the human brain suggests prion-like cell-to-cell spread. Neurobiol Dis. 2014.

16.

Chen L, Periquet M, Wang X, Negro A, McLean PJ, Hyman BT, et al. Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J Clin Invest. 2009;119(11):3257–65.PubMedCentralPubMed

17.

Hejjaoui M, Butterfield S, Fauvet B, Vercruysse F, Cui J, Dikiy I, et al. Elucidating the role of C-terminal post-translational modifications using protein semisynthesis strategies: α-synuclein phosphorylation at tyrosine 125. J Am Chem Soc. 2012;134(11):5196–210.PubMedCentralCrossRefPubMed

18.

Negro A, Brunati AM, Donella-Deana A, Massimino ML, Pinna LA. Multiple phosphorylation of α-synuclein by protein tyrosine kinase Syk prevents eosin-induced aggregation. FASEB J. 2002;16(2):210–2.PubMed

19.

Tai H-C, Schuman EM. Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat Rev Neurosci. 2008;9(11):826–38.CrossRefPubMed

20.

Komatsu M, Waguri S, Koike M, Sou Y-S, Ueno T, Hara T, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007;131(6):1149–63.CrossRefPubMed

21.

Doherty KM, Silveira-Moriyama L, Parkkinen L, Healy DG, Farrell M, Mencacci NE, et al. Parkin disease: a clinicopathologic entity? JAMA Neurol. 2013;70(5):571–9.PubMedCentralCrossRefPubMed

22.

Asi YT, Ling H, Ahmed Z, Lees AJ, Revesz T, Holton JL. Neuropathological features of multiple system atrophy with cognitive impairment. Mov Disord. 2014;29(7):884–8.CrossRefPubMed

23.

Kasten M, Klein C. The many faces of alpha-synuclein mutations. Mov Disord. 2013;28(6):697–701. doi:10.1002/mds.25499. Epub 2013 May 14.CrossRefPubMed

24.

Fuchs J, Nilsson C, Kachergus J, Munz M, Larsson E-M, Schüle B, et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology. 2007;68(12):916–22.CrossRefPubMed

25.

Nishioka K, Ross OA, Ishii K, Kachergus JM, Ishiwata K, Kitagawa M, et al. Expanding the clinical phenotype of SNCA duplication carriers. Mov Disord. 2009;24(12):1811–9.CrossRefPubMed

26.

Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, Sherman H, Yu I, Shah B, et al. Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson’s disease. Mov Disord. 2013;28(6):811–3.CrossRefPubMed

27.

Marui W, Iseki E, Nakai T, Miura S, Kato M, Uéda K, et al. Progression and staging of Lewy pathology in brains from patients with dementia with Lewy bodies. J Neurol Sci. 2002;195(2):153–9.CrossRefPubMed

28.

Braak H, Del Tredici K, Rub U, de Vos R, Jansen Steur E, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197–211.CrossRefPubMed

29.

Nakashima-Yasuda H, Uryu K, Robinson J, Xie S, Hurtig H, Duda J, et al. Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol. 2007;114(3):221–9.CrossRefPubMed

30.

Geser F, Malunda JA, Hurtig HI, Duda JE, Wenning GK, Gilman S, et al. TDP-43 pathology occurs infrequently in multiple system atrophy. Neuropathol Appl Neurobiol. 2011;37(4):358–65. Epub 2010/10/15.PubMedCentralCrossRefPubMed

31.

Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho W-H, Castillo PE, et al. Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000;25(1):239–52.CrossRefPubMed

32.

Rohan de Silva HA, Khan NL, Wood NW. The genetics of Parkinson’s disease. Curr Opin Genet Dev. 2000;10(3):292–8.CrossRef

33.

Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami K, et al. Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein α-synuclein. J Biol Chem. 2011;286(23):20710–26.PubMedCentralCrossRefPubMed

34.

Chandra S, Gallardo G, Fernández-Chacón R, Schlüter OM, Südhof TC. α-synuclein cooperates with CSPα in preventing neurodegeneration. Cell. 2005;123(3):383–96.CrossRefPubMed

35.

Anderson J, Walker D, Goldstein J, de Laat R, Banducci K, Caccavello R, et al. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem. 2006;281:29739–52.CrossRefPubMed

36.

Giasson BI, Duda JE, Murray IVJ, Chen Q, Souza JM, Hurtig HI, et al. Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions. Science. 2000;290(5493):985–9.CrossRefPubMed

37.

Tofaris GK, Razzaq A, Ghetti B, Lilley KS, Spillantini MG. Ubiquitination of α-synuclein in lewy bodies is a pathological event Not associated with impairment of proteasome function. J Biol Chem. 2003;278(45):44405–11.CrossRefPubMed

38.

Guerrero E, Vasudevaraju P, Hegde M, Britton GB, Rao KS. Recent advances in α-synuclein functions, advanced glycation, and toxicity: implications for Parkinson’s disease. Mol Neurobiol. 2013;47(2):525–36.CrossRefPubMed

39.

Yamashita S, Sakashita N, Yamashita T, Tawara N, Tasaki M, Kawakami K, et al. Concomitant accumulation of α-synuclein and TDP-43 in a patient with corticobasal degeneration. J Neurol. 2014;1–9.

40.

Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW. Colocalization of Tau and alpha-synuclein epitopes in lewy bodies. J Neuropathol Exp Neurol. 2003;62(4):389–97.PubMed

41.

Sengupta U, Guerrero-Muñoz MJ, Castillo-Carranza DL, Lasagna-Reeves CA, Gerson JE, Paulucci-Holthauzen AA, et al. Pathological interface between oligomeric alpha-synuclein and Tau in synucleinopathies. Biol Psychiatry. 2015.

42.

Hossain S, Alim A, Takeda K, Kaji H, Shinoda T, Ueda K. Limited proteolysis of NACP/alpha-synuclein. J Alzheimers Dis. 2001;3:577–84.PubMed

43.

Tenreiro S, Reimão-Pinto MM, Antas P, Rino J, Wawrzycka D, Macedo D, et al. Phosphorylation modulates clearance of alpha-synuclein inclusions in a yeast model of Parkinson’s disease. PLoS Genet. 2014;10(5), e1004302.PubMedCentralCrossRefPubMed

44.

Selkoe D, Dettmer U, Luth E, Kim N, Newman A, Bartels T. Defining the native state of α-synuclein. Neurodegener Dis. 2014;13(2–3):114–7.CrossRefPubMed

45.

Bartels T, Choi JG, Selkoe DJ. alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature. 2011;477(7362):107–10. Epub 2011/08/16.PubMedCentralCrossRefPubMed

46.

Dettmer U, Newman AJ, Luth ES, Bartels T, Selkoe D. In vivo cross-linking reveals principally oligomeric forms of α-synuclein and β-synuclein in neurons and Non-neural cells. J Biol Chem. 2013;288(9):6371–85.PubMedCentralCrossRefPubMed

47.

Burre J, Vivona S, Diao J, Sharma M, Brunger AT, Sudhof TC. Properties of native brain [agr]-synuclein. Nature. 2013;498(7453):E4–6.PubMedCentralCrossRefPubMed

48.

Atkin G, Paulson H. Ubiquitin pathways in neurodegenerative disease. Front Mol Neurosci. 2014;7:63. doi:10.3389/fnmol.2014.00063. eCollection 2014.PubMedCentralCrossRefPubMed

49.

Gao HM, Zhang F, Zhou H, Kam W, Wilson B, Hong JS. Neuroinflammation and alpha-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse model of Parkinson’s disease. Environ Health Perspect. 2011;119(6):807–14. Epub 2011/01/20.PubMedCentralCrossRefPubMed

50.

Brundin P, Li J-Y, Holton JL, Lindvall O, Revesz T. Research in motion: the enigma of Parkinson’s disease pathology spread. Nat Rev Neurosci. 2008;9(10):741–5.CrossRefPubMed

51.

Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW, et al. The E46K mutation in α-synuclein increases amyloid fibril formation. J Biol Chem. 2005;280(9):7800–7.CrossRefPubMed

52.

Choi W, Zibaee S, Jakes R, Serpell LC, Davletov B, Anthony Crowther R, et al. Mutation E46K increases phospholipid binding and assembly into filaments of human α-synuclein. FEBS Lett. 2004;576(3):363–8.CrossRefPubMed

53.

Conway KA, Harper JD, Lansbury PT. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med. 1998;4(11):1318–20. Epub 1998/11/11.CrossRefPubMed

54.

Conway KA, Lee S-J, Rochet J-C, Ding TT, Williamson RE, Lansbury PT. Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc Natl Acad Sci. 2000;97(2):571–6.PubMedCentralCrossRefPubMed

55.

Narhi L, Wood SJ, Steavenson S, Jiang Y, Wu GM, Anafi D, et al. Both familial Parkinson’s disease mutations accelerate α-synuclein aggregation. J Biol Chem. 1999;274(14):9843–6.CrossRefPubMed

56.

Fares M-B, Bouziad NA, Dikiy I, Mbefo MK, Jovičić A, Kiely A, et al. The novel Parkinson’s disease linked mutation G51D attenuates in vitro aggregation and membrane binding of α-synuclein, and enhances its secretion and nuclear localization in cells. Hum Mol Genet. 2014;23(17):4491–509.CrossRefPubMed

57.

Rutherford NJ, Moore BD, Golde TE, Giasson BI. Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of α-synuclein. J Neurochem. 2014;131(6):859–67.CrossRefPubMed

58.

Ghosh D, Sahay S, Ranjan P, Salot S, Mohite GM, Singh PK, et al. The newly discovered Parkinson’s disease associated Finnish mutation (A53E) attenuates α-synuclein aggregation and membrane binding. Biochemistry (Mosc). 2014;53(41):6419–21.CrossRef

59.

Chi Y-C, Armstrong GS, Jones DNM, Eisenmesser EZ, Liu C-W. Residue histidine 50 plays a Key role in protecting α-synuclein from aggregation at physiological pH. J Biol Chem. 2014;289(22):15474–81.PubMedCentralCrossRefPubMed

60.

Khalaf O, Fauvet B, Oueslati A, Dikiy I, Mahul-Mellier A-L, Ruggeri FS, et al. The H50Q mutation enhances α-synuclein aggregation, secretion, and toxicity. J Biol Chem. 2014;289(32):21856–76.PubMedCentralCrossRefPubMed

61.

Porcari R, Proukakis C, Waudby CA, Bolognesi B, Mangione PP, Paton JFS, et al. The H50Q mutation induces a 10-fold decrease in the solubility of α-synuclein. J Biol Chem. 2015;290(4):2395–404.PubMedCentralCrossRefPubMed

62.

Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, et al. In vivo demonstration that α-synuclein oligomers are toxic. Proc Natl Acad Sci. 2011;108(10):4194–9.PubMedCentralCrossRefPubMed

63.

Kalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE. α-Synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol. 2013;73(2):155–69.PubMedCentralCrossRefPubMed

64.

Markopoulou K, Dickson D, McComb R, Wszolek Z, Katechalidou L, Avery L, et al. Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease. Acta Neuropathol. 2008;116(1):25–35.PubMedCentralCrossRefPubMed

65.

Lemkau LR, Comellas G, Kloepper KD, Woods WS, George JM, Rienstra CM. Mutant protein A30P α-synuclein adopts wild-type fibril structure, despite slower fibrillation kinetics. J Biol Chem. 2012;287(14):11526–32.PubMedCentralCrossRefPubMed

66.

Seidel K, Schöls L, Nuber S, Petrasch-Parwez E, Gierga K, Wszolek Z, et al. First appraisal of brain pathology owing to A30P mutant alpha-synuclein. Ann Neurol. 2010;67(5):684–9.PubMed

67.

Obi T, Nishioka K, Ross OA, Terada T, Yamazaki K, Sugiura A, et al. Clincopathologic study of a SNCA gene duplication patient with Parkinson disease and dementia. Neurology. 2008;70(3):238–41.CrossRefPubMed

68.

Ikeuchi T, Kakita A, Shiga A, Kasuga K, Kaneko H, Tan CF, et al. Patients homozygous and heterozygous for snca duplication in a family with parkinsonism and dementia. Arch Neurol. 2008;65(4):514–9.CrossRefPubMed

69.

Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Yen SH, et al. Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol. 2000;99(6):663–72. Epub 2000/06/27.CrossRefPubMed

70.

Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, Kilford L, et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain. 2004;127(12):2657–71.CrossRefPubMed

Title: Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation
Authors: Aoife P. Kiely
Helen Ling
Yasmine T. Asi
Eleanna Kara
Christos Proukakis
Anthony H. Schapira
Huw R. Morris
Helen C. Roberts
Steven Lubbe
Patricia Limousin
Patrick A. Lewis
Andrew J. Lees
Niall Quinn
John Hardy
Seth Love
Tamas Revesz
Henry Houlden
Janice L. Holton
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Molecular Neurodegeneration / Issue 1/2015
Electronic ISSN: 1750-1326
DOI: https://doi.org/10.1186/s13024-015-0038-3

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Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

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