Abstract
Multiple system atrophy (MSA) is a unique proteinopathy that differs from other α-synucleinopathies since the pathological process resulting from accumulation of aberrant α-synuclein (αSyn) involves the oligodendroglia rather than neurons, although both pathologies affect multiple parts of the brain, spinal cord, autonomic and peripheral nervous system. Both the etiology and pathogenesis of MSA are unknown, although animal models have provided insight into the basic molecular changes of this disorder. Accumulation of aberrant αSyn in oligodendroglial cells and preceded by relocation of p25α protein from myelin to oligodendroglia results in the formation of insoluble glial cytoplasmic inclusions that cause cell dysfunction and demise. These changes are associated with proteasomal, mitochondrial and lipid transport dysfunction, oxidative stress, reduced trophic transport, neuroinflammation and other noxious factors. Their complex interaction induces dysfunction of the oligodendroglial-myelin-axon-neuron complex, resulting in the system-specific pattern of neurodegeneration characterizing MSA as a synucleinopathy with oligodendroglio-neuronopathy. Propagation of modified toxic αSyn species from neurons to oligodendroglia by “prion-like” transfer and its spreading associated with neuronal pathways result in a multi-system involvement. No reliable biomarkers are currently available for the clinical diagnosis and prognosis of MSA. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable diagnostic biomarkers and to deliver targets for effective treatment of this hitherto incurable disorder is urgently needed.
Similar content being viewed by others
Abbreviations
- αSyn:
-
α-Synuclein
- CSF:
-
Cerebrospinal fluid
- DLB:
-
Lewy body dementia
- GBA:
-
Glucocerebrosidase gene
- GCI:
-
Glial cytoplasmic inclusion
- GCIs:
-
Glial cytoplasmic inclusions
- LB:
-
Lewy body
- MBP:
-
Myelin basic protein
- MRI:
-
Magnetic resonance imaging
- MSA:
-
Multiple system atrophy
- MSA-C:
-
Cerebellar variant
- MSA-P:
-
Parkinsonian variant
- NCI:
-
Neuronal cytoplasmic inclusion
- NNI:
-
Neuronal nuclear inclusion
- OPCA:
-
Olivopontocerebellar atrophy
- OPC:
-
Oligodendroglial precursor cell
- OS:
-
Oxidative stress
- PD:
-
Parkinson disease
- PET:
-
Positron emission tomography
- PSP:
-
Progressive supranuclear palsy
- SND:
-
Striatonigral degeneration
- tg:
-
Transgene
- TPPP:
-
Tubulin polymerization promoting protein
- mRNA:
-
Mitochondrial ribonucleic acid
- miRNA:
-
Microribonucleic acid
References
Ahmed Z, Asi YT, Sailer A, Lees AJ, Houlden H, Revesz T, Holton JL (2012) The neuropathology, pathophysiology and genetics of multiple system atrophy. Neuropathol Appl Neurobiol 38:4–24
Ahmed Z, Asi YT, Lees AJ, Revesz T, Holton JL (2013) Identification and quantification of oligodendrocyte precursor cells in multiple system atrophy, progressive supranuclear palsy and Parkinson’s disease. Brain Pathol 23:263–273
Algarni MA, Stoessl AJ (2016) The role of biomarkers and imaging in Parkinson’s disease. Expert Rev Neurother 16:187–203
Alsemari A, Al-Hindi HN (2015) Large-scale mitochondrial DNA deletion underlying familial multiple system atrophy of the cerebellar subtype. Clin Case Rep 4:111–117
Aoki N, Boyer PJ, Lund C, Lin WL, Koga S, Ross OA, Weiner M, Lipton A, Powers JM, White CL 3rd, Dickson DW (2015) Atypical multiple system atrophy is a new subtype of frontotemporal lobar degeneration: frontotemporal lobar degeneration associated with alpha-synuclein. Acta Neuropathol 130:93–105
Asi YT, Ling H, Ahmed Z, Lees AJ, Revesz T, Holton JL (2014a) Neuropathological features of multiple system atrophy with cognitive impairment. Mov Disord 29:884–888
Asi YT, Simpson JE, Heath PR, Wharton SB, Lees AJ, Revesz T, Houlden H, Holton JL (2014b) Alpha-synuclein mRNA expression in oligodendrocytes in MSA. Glia 62:964–970
Barbagallo G, Sierra-Pena M, Nemmi F, Traon AP, Meissner WG, Rascol O, Peran P (2015) Multimodal MRI assessment of nigro-striatal pathway in multiple system atrophy and Parkinson disease. Mov Disord 31:325–334
Bassil F, Monvoisin A, Canron MH, Vital A, Meissner WG, Tison F, Fernagut PO (2015) Region-specific alterations of matrix metalloproteinase activity in multiple system atrophy. Mov Disord 30:1802–1812
Benarroch EE, Schmeichel AM, Low PA, Parisi JE (2010) Differential involvement of the periaqueductal gray in multiple system atrophy. Auton Neurosci 158:111–117
Beraud D, Hathaway HA, Trecki J, Chasovskikh S, Johnson DA, Johnson JA, Federoff HJ, Shimoji M, Mhyre TR, Maguire-Zeiss KA (2013) Microglial activation and antioxidant responses induced by the Parkinson’s disease protein alpha-synuclein. J Neuroimmune Pharmacol 8:94–117
Beyer K, Ariza A (2007) Protein aggregation mechanisms in synucleinopathies: commonalities and differences. J Neuropathol Exp Neurol 66:965–974
Blasco H, Nadal-Desbarats L, Pradat PF, Gordon PH, Madji Hounoum B, Patin F, Veyrat-Durebex C, Mavel S, Beltran S, Emond P, Andres CR, Corcia P (2016) Biomarkers in amyotrophic lateral sclerosis: combining metabolomic and clinical parameters to define disease progression. Eur J Neurol 23:346–353
Bleasel JM, Wong JH, Halliday GM, Kim WS (2014) Lipid dysfunction and pathogenesis of multiple system atrophy. Acta Neuropathol Commun 2:15
Bleasel JM, Halliday GM, Kim WS (2016) Animal modeling an oligodendrogliopathy—multiple system atrophy. Acta Neuropathol Commun 4:12
Blennow K, Zetterberg H (2015) The past and the future of Alzheimer’s disease CSF biomarkers-a journey toward validated biochemical tests covering the whole spectrum of molecular events. Front Neurosci 9:345
Brooks DJ, Seppi K (2009) Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov Disord 24:949–964
Bruck D, Wenning GK, Stefanova N, Fellner L (2016) Glia and alpha-synuclein in neurodegeneration: a complex interaction. Neurobiol Dis 85:262–274
Brudek T, Winge K, Rasmussen NB, Bahl JM, Tanassi J, Agander TK, Hyde TM, Pakkenberg B (2016) Altered alpha-synuclein, parkin, and synphilin isoform levels in multiple system atrophy brains. J Neurochem 136:172–185
Campbell BC, McLean CA, Culvenor JG, Gai WP, Blumbergs PC, Jakala P, Beyreuther K, Masters CL, Li QX (2001) The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. J Neurochem 76:87–96
Cao B, Zhao B, Wei QQ, Chen K, Yang J, Ou R, Wu Y, Shang HF (2015) The global cognition, frontal lobe dysfunction and behavior changes in chinese patients with multiple system atrophy. PLoS ONE 10:e0139773
Chavarria C, Souza JM (2013) Oxidation and nitration of alpha-synuclein and their implications in neurodegenerative diseases. Arch Biochem Biophys 533:25–32
Chelban V, Bettencourt C, Houlden H (2016) Updates on potential therapeutic targets in MSA. ACNR 15:8–11
Chen J, Mills JD, Halliday GM, Janitz M (2015a) Role of transcriptional control in multiple system atrophy. Neurobiol Aging 36:394–400
Chen YP, Zhao B, Cao B, Song W, Guo X, Wei QQ, Yang Y, Yuan LX, Shang HF (2015b) Mutation scanning of the COQ2 gene in ethnic Chinese patients with multiple-system atrophy. Neurobiol Aging 36:1222.e7–1222.e11
Chung EJ, Lee WY, Yoon WT, Kim BJ, Lee GH (2009) MIBG scintigraphy for differentiating Parkinson’s disease with autonomic dysfunction from Parkinsonism-predominant multiple system atrophy. Mov Disord 24:1650–1655
Coon EA, Sletten DM, Suarez MD, Mandrekar JN, Ahlskog JE, Bower JH, Matsumoto JY, Silber MH, Benarroch EE, Fealey RD, Sandroni P, Low PA, Singer W (2015) Clinical features and autonomic testing predict survival in multiple system atrophy. Brain 138:3623–3631
Costa J, de Carvalho M (2016) Emerging molecular biomarker targets for amyotrophic lateral sclerosis. Clin Chim Acta 455:7–14
Cykowski MD, Coon EA, Powell SZ, Jenkins SM, Benarroch EE, Low PA, Schmeichel AM, Parisi JE (2015) Expanding the spectrum of neuronal pathology in multiple system atrophy. Brain 138:2293–2309
Dehay B, Vila M, Bezard E, Brundin P, Kordower JH (2016) Alpha-synuclein propagation: new insights from animal models. Mov Disord 31:161–168
Delenclos M, Jones DR, McLean PJ, Uitti RJ (2016) Biomarkers in Parkinson’s disease: advances and strategies. Parkinsonism Relat Disord 22(Suppl 1):S106–S110
Dickson DW, Liu W, Hardy J, Farrer M, Mehta N, Uitti R, Mark M, Zimmerman T, Golbe L, Sage J, Sima A, D’Amato C, Albin R, Gilman S, Yen SH (1999) Widespread alterations of alpha-synuclein in multiple system atrophy. Am J Pathol 155:1241–1251
Djelloul M, Holmqvist S, Boza-Serrano A, Azevedo C, Yeung MS, Goldwurm S, Frisen J, Deierborg T, Roybon L (2015) Alpha-synuclein expression in the oligodendrocyte lineage: an in vitro and in vivo study using rodent and human models. Stem Cell Reports 5:174–184
Don AS, Hsiao JH, Bleasel JM, Couttas TA, Halliday GM, Kim W (2014) Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy. Acta Neuropathol Commun 2:150
Doppler K, Weis J, Karl K, Ebert S, Ebentheuer J, Trenkwalder C, Klebe S, Volkmann J, Sommer C (2015) Distinctive distribution of phospho-alpha-synuclein in dermal nerves in multiple system atrophy. Mov Disord 30:1688–1692
Duda JE, Giasson BI, Gur TL, Montine TJ, Robertson D, Biaggioni I, Hurtig HI, Stern MB, Gollomp SM, Grossman M, Lee VM, Trojanowski JQ (2000) Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy. J Neuropathol Exp Neurol 59:830–841
Ettle B, Reiprich S, Deusser J, Schlachetzki JC, Xiang W, Prots I, Masliah E, Winner B, Wegner M, Winkler J (2014) Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells. Mol Cell Neurosci 62:68–78
Ettle B, Kerman BE, Valera E, Gillmann C, Schlachetzki JCM, Reiprich S, Büttner C, Ekici AB, Reis A, Wegner M, Bäuerle T, Riemenschneider MJ, Masliah E, Gage FH, Winkler J (2016) α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy. Acta Neuropathol. doi:10.1007/s00401-016-1572-y
Fanciulli A, Wenning GK (2015) Multiple-system atrophy. N Engl J Med 372:249–263
Federoff M, Price TR, Sailer A, Scholz S, Hernandez D, Nicolas A, Singleton AB, Nalls M, Houlden H (2016) Genome-wide estimate of the heritability of multiple system atrophy. Parkinsonism Relat Disord 22:35–41
Fellner L, Jellinger KA, Wenning GK, Stefanova N (2011) Glial dysfunction in the pathogenesis of alpha-synucleinopathies: emerging concepts. Acta Neuropathol 121:675–693
Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W, Wenning GK, Stefanova N (2013) Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61:349–360
Fellner L, Wenning GK, Stefanova N (2015) Models of multiple system atrophy. Curr Top Behav Neurosci 22:369–393
Ferguson MC, Garland EM, Hedges L, Womack-Nunley B, Hamid R, Phillips JA 3rd, Shibao CA, Raj SR, Biaggioni I, Robertson D (2014) SHC2 gene copy number in multiple system atrophy (MSA). Clin Auton Res 24:25–30
Fujioka S, Ogaki K, Tacik PM, Uitti RJ, Ross OA, Wszolek ZK (2014) Update on novel familial forms of Parkinson’s disease and multiple system atrophy. Parkinsonism Relat Disord 20(Suppl 1):S29–S34
Fujishiro H, Imamura AY, Lin WL, Uchikado H, Mark MH, Golbe LI, Markopoulou K, Wszolek ZK, Dickson DW (2013) Diversity of pathological features other than Lewy bodies in familial Parkinson’s disease due to SNCA mutations. Am J Neurodegener Dis 2:266–275
Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164
Furukawa Y, Vigouroux S, Wong H, Guttman M, Rajput AH, Ang L, Briand M, Kish SJ, Briand Y (2002) Brain proteasomal function in sporadic Parkinson’s disease and related disorders. Ann Neurol 51:779–782
Geser F, Malunda JA, Hurtig HI, Duda JE, Wenning GK, Gilman S, Low PA, Lee VM-Y, Trojanowski JQ (2011) TDP-43 pathology occurs infrequently in multiple system atrophy. Neuropathol Appl Neurobiol 37:358–365
Giasson BI, Mabon ME, Duda JE, Montine TJ, Robertson D, Hurtig HI, Lee VM, Trojanowski JQ (2003) Tau and 14-3-3 in glial cytoplasmic inclusions of multiple system atrophy. Acta Neuropathol 106:243–250
Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676
Goldstein DS, Sullivan P, Holmes C, Kopin IJ, Sharabi Y, Mash DC (2015) Decreased vesicular storage and aldehyde dehydrogenase activity in multiple system atrophy. Parkinsonism Relat Disord 21:567–572
Haga R, Sugimoto K, Nishijima H, Miki Y, Suzuki C, Wakabayashi K, Baba M, Yagihashi S, Tomiyama M (2015) Clinical utility of skin biopsy in differentiating between Parkinson’s disease and multiple system atrophy. Parkinsons Dis 2015:167038
Halliday GM (2015) Re-evaluating the glio-centric view of multiple system atrophy by highlighting the neuronal involvement. Brain 138:2116–2119
Halliday GM, Holton JL, Revesz T, Dickson DW (2011) Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol 122:187–204
Hara K, Momose Y, Tokiguchi S, Shimohata M, Terajima K, Onodera O, Kakita A, Yamada M, Takahashi H, Hirasawa M, Mizuno Y, Ogata K, Goto J, Kanazawa I, Nishizawa M, Tsuji S (2007) Multiplex families with multiple system atrophy. Arch Neurol 64:545–551
Hasegawa M, Fujiwara H, Nonaka T, Wakabayashi K, Takahashi H, Lee VM, Trojanowski JQ, Mann D, Iwatsubo T (2002) Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions. J Biol Chem 277:49071–49076
Hayakawa H, Nagai M, Kawanami A, Nakata Y, Nihira T, Ogino M, Takada M, Saido T, Takano J, Saegusa M, Mikami T, Hamada J, Nishiyama K, Mochizuki H, Mizuno Y (2013) Loss of DARPP-32 and calbindin in multiple system atrophy. J Neural Transm (Vienna) 120:1689–1698
Heckman MG, Schottlaender L, Soto-Ortolaza AI, Diehl NN, Rayaprolu S, Ogaki K, Fujioka S, Murray ME, Cheshire WP, Uitti RJ, Wszolek ZK, Farrer MJ, Sailer A, Singleton AB, Chinnery PF, Keogh MJ, Gentleman SM, Holton JL, Aoife K, Mann DM, Al-Sarraj S, Troakes C, Dickson DW, Houlden H, Ross OA (2014) LRRK2 exonic variants and risk of multiple system atrophy. Neurology 83:2256–2261
Helwig M, Klinkenberg M, Rusconi R, Musgrove RE, Majbour NK, El-Agnaf OM, Ulusoy A, Di Monte DA (2016) Brain propagation of transduced alpha-synuclein involves non-fibrillar protein species and is enhanced in alpha-synuclein null mice. Brain 139:856–870
Herbert MK, Eeftens JM, Aerts MB, Esselink RA, Bloem BR, Kuiperij HB, Verbeek MM (2014) CSF levels of DJ-1 and tau distinguish MSA patients from PD patients and controls. Parkinsonism Relat Disord 20:112–115
Herbert MK, Aerts MB, Beenes M, Norgren N, Esselink RA, Bloem BR, Kuiperij HB, Verbeek MM (2015) CSF neurofilament light chain but not FLT3 ligand discriminates Parkinsonian disorders. Front Neurol 6:91
Hoglund K, Fourier A, Perret-Liaudet A, Zetterberg H, Blennow K, Portelius E (2015) Alzheimer’s disease—recent biomarker developments in relation to updated diagnostic criteria. Clin Chim Acta 449:3–8
Homma T, Mochizuki Y, Komori T, Isozaki E (2016) Frequent globular neuronal cytoplasmic inclusions in the medial temporal region as a possible characteristic feature in multiple system atrophy with dementia. Neuropathology. doi:10.1111/neup.12289
Indelicato E, Fanciulli A, Poewe W, Antonini A, Pontieri FE, Wenning GK (2015) Cerebral autoregulation and white matter lesions in Parkinson’s disease and multiple system atrophy. Parkinsonism Relat Disord 21:1393–1397
Iodice V, Lipp A, Ahlskog JE, Sandroni P, Fealey RD, Parisi JE, Matsumoto JY, Benarroch EE, Kimpinski K, Singer W, Gehrking TL, Gehrking JA, Sletten DM, Schmeichel AM, Bower JH, Gilman S, Figueroa J, Low PA (2012) Autopsy confirmed multiple system atrophy cases: mayo experience and role of autonomic function tests. J Neurol Neurosurg Psychiatry 83:453–459
Ishizawa K, Komori T, Arai N, Mizutani T, Hirose T (2008) Glial cytoplasmic inclusions and tissue injury in multiple system atrophy: a quantitative study in white matter (olivopontocerebellar system) and gray matter (nigrostriatal system). Neuropathology 28:249–257
Jecmenica-Lukic M, Poewe W, Tolosa E, Wenning GK (2012) Premotor signs and symptoms of multiple system atrophy. Lancet Neurol 11:361–368
Jellinger KA (2007) More frequent Lewy bodies but less frequent Alzheimer-type lesions in multiple system atrophy as compared to age-matched control brains. Acta Neuropathol 114:299–303
Jellinger KA (2014) Neuropathology of multiple system atrophy: new thoughts about pathogenesis. Mov Disord 29:1720–1741
Jellinger KA (2015a) Neuropathology and pathogenesis of multiple system atrophy: an update. Curr Trends Neurol 9:45–54
Jellinger KA (2015b) Multiple system atrophy—a synucleinopathy with specific glioneuronal degeneration. Austin J Clin Neurol 2:1071
Jellinger KA (2015c) What’s new in multiple system atrophy. Curr Neurobiol 6:11–14
Jellinger KA (2016) Recent advances in multiple system atrophy. J Neurol Neuromed 1:6–17
Jellinger KA, Krismer F (2014) Aetiopathogenesis. In: Wenning GK, Fanciulli A (eds) Multiple system atrophy. Springer, Vienna, pp 57–81
Jellinger KA, Lantos PL (2010) Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update. Acta Neuropathol 119:657–667
Jellinger KA, Seppi K, Wenning GK (2005) Grading of neuropathology in multiple system atrophy: proposal for a novel scale. Mov Disord 20(Suppl 12):S29–S36
Ji L, Wang Y, Zhu D, Liu W, Shi J (2015) White matter differences between multiple system atrophy (parkinsonian type) and Parkinson’s disease: a diffusion tensor image study. Neuroscience 305:109–116
Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W, Fuss B, Mallon B, Macklin WB, Fujiwara H, Hasegawa M, Iwatsubo T, Kretzschmar HA, Haass C (2002) Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 3:583–588
Kaindlstorfer C, Krismer F, Fanciulli A, Eschlböck S, Nocker M, Bösch S, Mair K, Scherfler C, Djamshidian-Tehrani A, Uprimny C, Donnemiller E, Virgolini I, Seppi K, Poewe W, Wenning G (2016) Diagnostic value of cardiac 123I-MIBG SPECT and CT co-registration in PD and MSA-P (Poster). Neurol Suppl 1:38
Kang JH, Korecka M, Figurski MJ, Toledo JB, Blennow K, Zetterberg H, Waligorska T, Brylska M, Fields L, Shah N, Soares H, Dean RA, Vanderstichele H, Petersen RC, Aisen PS, Saykin AJ, Weiner MW, Trojanowski JQ, Shaw LM (2015) The Alzheimer’s disease neuroimaging initiative 2 biomarker core: a review of progress and plans. Alzheimers Dement 11:772–791
Kasahara S, Miki Y, Kanagaki M, Kondo T, Yamamoto A, Morimoto E, Okada T, Ito H, Takahashi R, Togashi K (2012) “Hot cross bun” sign in multiple system atrophy with predominant cerebellar ataxia: a comparison between proton density-weighted imaging and T2-weighted imaging. Eur J Radiol 81:2848–2852
Kasai T, Tokuda T, Ohmichi T, Ishii R, Tatebe H, Nakagawa M, Mizuno T (2016) Serum levels of coenzyme Q10 in patients with multiple system atrophy. PLoS ONE 11:e0147574
Kawamoto Y, Ito H, Ihara M, Takahashi R (2014) XIAP immunoreactivity in glial and neuronal cytoplasmic inclusions in multiple system atrophy. Clin Neuropathol 33:76–83
Kiely AP, Asi YT, Kara E, Limousin P, Ling H, Lewis P, Proukakis C, Quinn N, Lees AJ, Hardy J, Revesz T, Houlden H, Holton JL (2013) alpha-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy? Acta Neuropathol 125:753–769
Kiely AP, Ling H, Asi YT, Kara E, Proukakis C, Schapira AH, Morris HR, Roberts HC, Lubbe S, Limousin P, Lewis PA, Lees AJ, Quinn N, Hardy J, Love S, Revesz T, Houlden H, Holton JL (2015) Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation. Mol Neurodegener 10:41
Kiely AP, Murray c, Asi YT, Ahmed Z, Lashley T, Revesz T, Holton JL (2016) NanoString analysis of neuroinflammation in multiple system atrophy (abstr.). Neuropathol Appl Neurobiol 42 suppl 1:36
Kikuchi A, Takeda A, Okamura N, Tashiro M, Hasegawa T, Furumoto S, Kobayashi M, Sugeno N, Baba T, Miki Y, Mori F, Wakabayashi K, Funaki Y, Iwata R, Takahashi S, Fukuda H, Arai H, Kudo Y, Yanai K, Itoyama Y (2010) In vivo visualization of alpha-synuclein deposition by carbon-11-labelled 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy]benzoxazole positron emission tomography in multiple system atrophy. Brain 133:1772–1778
Kim HJ, Jeon BS, Jellinger KA (2015a) Diagnosis and differential diagnosis of MSA: boundary issues. J Neurol 262:1801–1813
Kim JS, Yang JJ, Lee DK, Lee JM, Youn J, Cho JW (2015b) Cognitive impairment and its structural correlates in the parkinsonian subtype of multiple system atrophy. Neurodegener Dis 15:294–300
Kim HJ, Stamelou M, Jeon B (2016a) Multiple system atrophy-mimicking conditions: diagnostic challenges. Parkinsonism Relat Disord 22(Suppl 1):S12–S15
Kim HW, Kim JS, Oh M, Oh JS, Lee SJ, Oh SJ, Chung SJ, Lee CS (2016b) Different loss of dopamine transporter according to subtype of multiple system atrophy. Eur J Nucl Med Mol Imaging 43:517–525
Kim JM, Jeong HJ, Bae YJ, Park SY, Kim E, Kang SY, Oh ES, Kim KJ, Jeon B, Kim SE, Cho ZH, Kim YB (2016c) Loss of substantia nigra hyperintensity on 7 Tesla MRI of Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Parkinsonism Relat Disord. doi:10.1016/j.parkreldis.2016.01.023
King AE, Mintz J, Royall DR (2011) Meta-analysis of 123I-MIBG cardiac scintigraphy for the diagnosis of Lewy body-related disorders. Mov Disord 26:1218–1224
Kisos H, Pukass K, Ben-Hur T, Richter-Landsberg C, Sharon R (2012) Increased neuronal alpha-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling alpha-synucleinopathies. PLoS ONE 7:e46817
Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, Wszolek ZK, Langston JW, Dickson DW (2015) When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients. Neurology 85:404–412
Köllensperger M, Geser F, Ndayisaba JP, Boesch S, Seppi K, Ostergaard K, Dupont E, Cardozo A, Tolosa E, Abele M, Klockgether T, Yekhlef F, Tison F, Daniels C, Deuschl G, Coelho M, Sampaio C, Bozi M, Quinn N, Schrag A, Mathias CJ, Fowler C, Nilsson CF, Widner H, Schimke N, Oertel W, Del Sorbo F, Albanese A, Pellecchia MT, Barone P, Djaldetti R, Colosimo C, Meco G, Gonzalez-Mandly A, Berciano J, Gurevich T, Giladi N, Galitzky M, Rascol O, Kamm C, Gasser T, Siebert U, Poewe W, Wenning GK (2010) Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry. Mov Disord 25:2604–2612
Kon T, Mori F, Tanji K, Miki Y, Wakabayashi K (2013) An autopsy case of preclinical multiple system atrophy (MSA-C). Neuropathology 33:667–672
Kovacs GG, Breydo L, Green R, Kis V, Puska G, Lorincz P, Perju-Dumbrava L, Giera R, Pirker W, Lutz M, Lachmann I, Budka H, Uversky VN, Molnar K, Laszlo L (2014) Intracellular processing of disease-associated alpha-synuclein in the human brain suggests prion-like cell-to-cell spread. Neurobiol Dis 69:76–92
Kragh CL, Gysbers AM, Rockenstein E, Murphy K, Halliday GM, Masliah E, Jensen PH (2014) Prodegenerative IkappaBalpha expression in oligodendroglial alpha-synuclein models of multiple system atrophy. Neurobiol Dis 63:171–183
Kuzdas D, Stemberger S, Gaburro S, Stefanova N, Singewald N, Wenning GK (2013) Oligodendroglial alpha-synucleinopathy and MSA-like cardiovascular autonomic failure: experimental evidence. Exp Neurol 247:531–536
Kuzdas-Wood D, Stefanova N, Jellinger KA, Seppi K, Schlossmacher MG, Poewe W, Wenning GK (2014) Towards translational therapies for multiple system atrophy. Prog Neurobiol 118C:19–35
Kuzdas-Wood D, Fellner L, Premstaller M, Borm C, Bloem B, Kirik D, Wenning GK, Stefanova N (2015) Overexpression of alpha-synuclein in oligodendrocytes does not increase susceptibility to focal striatal excitotoxicity. BMC Neurosci 16:86
Laurens B, Constantinescu R, Freeman R, Gerhard A, Jellinger K, Jeromin A, Krismer F, Mollenhauer B, Schlossmacher MG, Shaw LM, Verbeek MM, Wenning GK, Winge K, Zhang J, Meissner WG (2015) Fluid biomarkers in multiple system atrophy: a review of the MSA Biomarker Initiative. Neurobiol Dis 80:29–41
Lee SW, Koh SB (2012) Clinical features and disability milestones in multiple system atrophy and progressive supranuclear palsy. J Mov Disord 5:42–47
Lee JH, Kim TH, Mun CW, Han YH (2015) Progression of subcortical atrophy and iron deposition in multiple system atrophy: a comparison between clinical subtypes. J Neurol 262:1876–1882. doi:10.1007/s00415-015-7785-5
Ling H, Asi YT, Petrovic IN, Ahmed Z, Prashanth LK, Hazrati LN, Nishizawa M, Ozawa T, Lang A, Lees AJ, Revesz T, Holton JL (2015) Minimal change multiple system atrophy: an aggressive variant? Mov Disord 30:960–967
Lista S, Garaci FG, Ewers M, Teipel S, Zetterberg H, Blennow K, Hampel H (2014) CSF Abeta1-42 combined with neuroimaging biomarkers in the early detection, diagnosis and prediction of Alzheimer’s disease. Alzheimers Dement 10:381–392
Lu CF, Wang PS, Lao YL, Wu HM, Soong BW, Wu YT (2014) Medullo-ponto-cerebellar white matter degeneration altered brain network organization and cortical morphology in multiple system atrophy. Brain Struct Funct 219:947–958
Magdalinou NK, Paterson RW, Schott JM, Fox NC, Mummery C, Blennow K, Bhatia K, Morris HR, Giunti P, Warner TT, de Silva R, Lees AJ, Zetterberg H (2015) A panel of nine cerebrospinal fluid biomarkers may identify patients with atypical parkinsonian syndromes. J Neurol Neurosurg Psychiatry 86:1240–1247
Majbour NK, Vaikath NN, van Dijk KD, Ardah MT, Varghese S, Vesterager LB, Montezinho LP, Poole S, Safieh-Garabedian B, Tokuda T, Teunissen CE, Berendse HW, van de Berg WD, El-Agnaf OM (2016) Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson’s disease. Mol Neurodegener 11:7
Masuda-Suzukake M, Nonaka T, Hosokawa M, Kubo M, Shimozawa A, Akiyama H, Hasegawa M (2014) Pathological alpha-synuclein propagates through neural networks. Acta Neuropathol Commun 2:88
Masui K, Nakata Y, Fujii N, Iwaki T (2012) Extensive distribution of glial cytoplasmic inclusions in an autopsied case of multiple system atrophy with a prolonged 18-year clinical course. Neuropathology 32:69–76
May VE, Ettle B, Poehler AM, Nuber S, Ubhi K, Rockenstein E, Winner B, Wegner M, Masliah E, Winkler J (2014) alpha-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy. Neurobiol Aging 35:2357–2368
McCann H, McGeachie AB, Silberstein P, Lewis SJ, Halliday GM (2015) Restricted disease propagation in multiple system atrophy with prolonged survival. Neuropathol Appl Neurobiol 41:681–685
McCormack A, Chegeni N, Chegini F, Colella A, Power J, Keating D, Chataway T (2016) Purification of alpha-synuclein containing inclusions from human post mortem brain tissue. J Neurosci Methods. doi:10.1016/j.jneumeth.2016.03.016
Mendoza-Santiesteban CE, Palma JA, Martinez J, Norcliffe-Kaufmann L, Hedges TR 3rd, Kaufmann H (2015) Progressive retinal structure abnormalities in multiple system atrophy. Mov Disord 30:1944–1953
Mestre TA, Gupta A, Lang AE (2016) MRI signs of multiple system atrophy preceding the clinical diagnosis: the case for an imaging-supported probable MSA diagnostic category. J Neurol Neurosurg Psychiatry 87:443–444
Miller DB, O’Callaghan JP (2015) Biomarkers of Parkinson’s disease: present and future. Metabolism 64:S40–S46
Mills JD, Kim WS, Halliday GM, Janitz M (2015) Transcriptome analysis of grey and white matter cortical tissue in multiple system atrophy. Neurogenetics 16:107–122
Mills JD, Ward M, Kim WS, Halliday GM, Janitz M (2016) Strand-specific RNA-sequencing analysis of multiple system atrophy brain transcriptome. Neuroscience 322:234–250
Mitsui J, Matsukawa T, Sasaki H, Yabe I, Matsushima M, Durr A, Brice A, Takashima H, Kikuchi A, Aoki M, Ishiura H, Yasuda T, Date H, Ahsan B, Iwata A, Goto J, Ichikawa Y, Nakahara Y, Momose Y, Takahashi Y, Hara K, Kakita A, Yamada M, Takahashi H, Onodera O, Nishizawa M, Watanabe H, Ito M, Sobue G, Ishikawa K, Mizusawa H, Kanai K, Hattori T, Kuwabara S, Arai K, Koyano S, Kuroiwa Y, Hasegawa K, Yuasa T, Yasui K, Nakashima K, Ito H, Izumi Y, Kaji R, Kato T, Kusunoki S, Osaki Y, Horiuchi M, Kondo T, Murayama S, Hattori N, Yamamoto M, Murata M, Satake W, Toda T, Filla A, Klockgether T, Wullner U, Nicholson G, Gilman S, Tanner CM, Kukull WA, Stern MB, Lee VM, Trojanowski JQ, Masliah E, Low PA, Sandroni P, Ozelius LJ, Foroud T, Tsuji S (2015) Variants associated with Gaucher disease in multiple system atrophy. Ann Clin Transl Neurol 2:417–426
Molinuevo JL, Blennow K, Dubois B, Engelborghs S, Lewczuk P, Perret-Liaudet A, Teunissen CE, Parnetti L (2014) The clinical use of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: a consensus paper from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimers Dement 10:808–817
Mollenhauer B, Parnetti L, Rektorova I, Kramberger MG, Pikkarainen M, Schulz-Schaeffer WJ, Aarsland D, Svenningsson P, Farotti L, Verbeek MM, Schlossmacher MG (2015) Biological confounders for the values of cerebrospinal fluid proteins in Parkinson’s disease and related disorders. J Neurochem. doi:10.1111/jnc.13390
Nagayama H, Ueda M, Yamazaki M, Nishiyama Y, Hamamoto M, Katayama Y (2010) Abnormal cardiac [(123)I]-meta-iodobenzylguanidine uptake in multiple system atrophy. Mov Disord 25:1744–1747
Nakamura K, Mori F, Kon T, Tanji K, Miki Y, Tomiyama M, Kurotaki H, Toyoshima Y, Kakita A, Takahashi H, Yamada M, Wakabayashi K (2015a) Accumulation of phosphorylated alpha-synuclein in subpial and periventricular astrocytes in multiple system atrophy of long duration. Neuropathology. doi:10.1111/neup.12243 (in print)
Nakamura K, Mori F, Kon T, Tanji K, Miki Y, Tomiyama M, Kurotaki H, Toyoshima Y, Kakita A, Takahashi H, Yamada M, Wakabayashi K (2015b) Filamentous aggregations of phosphorylated alpha-synuclein in Schwann cells (Schwann cell cytoplasmic inclusions) in multiple system atrophy. Acta Neuropathol Commun 3:29
Nakayama K, Suzuki Y, Yazawa I (2012) Binding of neuronal alpha-synuclein to beta-III tubulin and accumulation in a model of multiple system atrophy. Biochem Biophys Res Commun 417:1170–1175
Ogaki K, Fujioka S, Heckman MG, Rayaprolu S, Soto-Ortolaza AI, Labbe C, Walton RL, Lorenzo-Betancor O, Wang X, Asmann Y, Rademakers R, Graff-Radford N, Uitti R, Cheshire WP, Wszolek ZK, Dickson DW, Ross OA (2014) Analysis of COQ2 gene in multiple system atrophy. Mol Neurodegener 9:44
Orimo S, Suzuki M, Inaba A, Mizusawa H (2012) 123I-MIBG myocardial scintigraphy for differentiating Parkinson’s disease from other neurodegenerative parkinsonism: a systematic review and meta-analysis. Parkinsonism Relat Disord 18:494–500
Ota K, Obayashi M, Ozaki K, Ichinose S, Kakita A, Tada M, Takahashi H, Ando N, Eishi Y, Mizusawa H, Ishikawa K (2014) Relocation of p25 inverted question mark/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy. Acta Neuropathol Commun 2:136
Ovadi J, Orosz F (2009) An unstructured protein with destructive potential: TPPP/p25 in neurodegeneration. BioEssays 31:676–686
Ozawa T (2006) Pathology and genetics of multiple system atrophy: an approach to determining genetic susceptibility spectrum. Acta Neuropathol 112:531–538
Ozawa T (2007) Morphological substrate of autonomic failure and neurohormonal dysfunction in multiple system atrophy: impact on determining phenotype spectrum. Acta Neuropathol 114:201–211
Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, Kilford L, Healy DG, Wood NW, Lees AJ, Holton JL, Revesz T (2004) The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 127:2657–2671
Palma JA, Fernandez-Cordon C, Coon EA, Low PA, Miglis MG, Jaradeh S, Bhaumik AK, Dayalu P, Urrestarazu E, Iriarte J, Biaggioni I, Kaufmann H (2015) Prevalence of REM sleep behavior disorder in multiple system atrophy: a multicenter study and meta-analysis. Clin Auton Res 25:69–75
Parnetti L, Cicognola C, Eusebi P, Chiasserini D (2016) Value of cerebrospinal fluid alpha-synuclein species as biomarker in Parkinson’s diagnosis and prognosis. Biomark Med 10:35–49
Pasanen P, Myllykangas L, Siitonen M, Raunio A, Kaakkola S, Lyytinen J, Tienari PJ, Poyhonen M, Paetau A (2014) A novel alpha-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson’s disease-type pathology. Neurobiol Aging 35(2180):e2181–e2185
Peelaerts W, Baekelandt V (2016) a-Synuclein strains and the variable pathologies of synucleinopathies. J Neurochem. doi:10.1111/jnc.13595 (in print)
Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M, Van den Haute C, Melki R, Baekelandt V (2015) alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340–344
Perju-Dumbrava LD, Kovacs GG, Pirker S, Jellinger K, Hoffmann M, Asenbaum S, Pirker W (2012) Dopamine transporter imaging in autopsy-confirmed Parkinson’s disease and multiple system atrophy. Mov Disord 27:65–71
Petrovic IN, Ling H, Asi Y, Ahmed Z, Kukkle PL, Hazrati LN, Lang AE, Revesz T, Holton JL, Lees AJ (2012) Multiple system atrophy-parkinsonism with slow progression and prolonged survival: a diagnostic catch. Mov Disord 27:1186–1190
Pouclet H, Lebouvier T, Coron E, Rouaud T, Flamant M, Toulgoat F, Roy M, Vavasseur F, Bruley des Varannes S, Neunlist M, Derkinderen P (2012) Analysis of colonic alpha-synuclein pathology in multiple system atrophy. Parkinsonism Relat Disord 18:893–895
Provitera V, Nolano M, Caporaso G, Stancanelli A, Manganelli F, Iodice R, Selim MM, De Rosa A, Lanzillo B, Pellecchia MT, De Michele G, Santoro L (2014) Postganglionic sudomotor denervation in patients with multiple system atrophy. Neurology 82:2223–2229
Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH, Glidden DV, Halliday GM, Middleton LT, Gentleman SM, Grinberg LT, Giles K (2015) Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci USA 112:E5308–E5317
Pukass K, Richter-Landsberg C (2015) Inhibition of UCH-L1 in oligodendroglial cells results in microtubule stabilization and prevents alpha-synuclein aggregate formation by activating the autophagic pathway: implications for multiple system atrophy. Front Cell Neurosci 9:163
Ramli N, Nair SR, Ramli NM, Lim SY (2015) Differentiating multiple-system atrophy from Parkinson’s disease. Clin Radiol 70:555–564
Rey NL, George S, Brundin P (2016) Review: spreading the word: precise animal models and validated methods are vital when evaluating prion-like behaviour of alpha-synuclein. Neuropathol Appl Neurobiol 42:51–76
Reyes JF, Rey NL, Bousset L, Melki R, Brundin P, Angot E (2014) Alpha-synuclein transfers from neurons to oligodendrocytes. Glia 62:387–398
Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM (2000) alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62:9–14
Rizzo G, Copetti M, Arcuti S, Martino D, Fontana A, Logroscino G (2016) Accuracy of clinical diagnosis of Parkinson disease: a systematic review and meta-analysis. Neurology 86:566–576
Rockenstein E, Ubhi K, Inglis C, Mante M, Patrick C, Adame A, Masliah E (2012) Neuronal to oligodendroglial alpha-synuclein redistribution in a double transgenic model of multiple system atrophy. Neuroreport 23:259–264
Rohan Z, Rahimi J, Weis S, Kapas I, Auff E, Mitrovic N, Liberski PP, Sikorska B, Matej R, Kovacs GG (2015) Screening for alpha-synuclein immunoreactive neuronal inclusions in the hippocampus allows identification of atypical MSA (FTLD-synuclein). Acta Neuropathol 130:299–301
Roncevic D, Palma JA, Martinez J, Goulding N, Norcliffe-Kaufmann L, Kaufmann H (2014) Cerebellar and parkinsonian phenotypes in multiple system atrophy: similarities, differences and survival. J Neural Transm 121:507–512
Ross OA, Vilarino-Guell C, Wszolek ZK, Farrer MJ, Dickson DW (2010) Reply to: SNCA variants are associated with increased risk of multiple system atrophy. Ann Neurol 67:414–415
Sacino AN, Brooks M, Thomas MA, McKinney AB, McGarvey NH, Rutherford NJ, Ceballos-Diaz C, Robertson J, Golde TE, Giasson BI (2014) Amyloidogenic alpha-synuclein seeds do not invariably induce rapid, widespread pathology in mice. Acta Neuropathol 127:645–665
Sako W, Murakami N, Izumi Y, Kaji R (2016) The difference of apparent diffusion coefficient in the middle cerebellar peduncle among parkinsonian syndromes: Evidence from a meta-analysis. J Neurol Sci 363:90–94
Salvesen L, Ullerup BH, Sunay FB, Brudek T, Lokkegaard A, Agander TK, Winge K, Pakkenberg B (2015a) Changes in total cell numbers of the basal ganglia in patients with multiple system atrophy—a stereological study. Neurobiol Dis 74:104–113
Salvesen L, Winge K, Brudek T, Agander TK, Lokkegaard A, Pakkenberg B (2015b) Neocortical neuronal loss in patients with multiple system atrophy: a stereological study. Cereb Cortex. doi:10.1093/cercor/bhv1228 (in print)
Sasaki H, Emi M, Iijima H, Ito N, Sato H, Yabe I, Kato T, Utsumi J, Matsubara K (2011) Copy number loss of (src homology 2 domain containing)-transforming protein 2 (SHC2) gene: discordant loss in monozygotic twins and frequent loss in patients with multiple system atrophy. Mol Brain 4:24
Schafferer S, Khurana R, Refolo V, Venezia S, Sturm E, Piatti P, Hechenberger C, Hackl H, Kessler R, Willi M, Gstir R, Krogsdam A, Lusser A, Poewe W, Wenning GK, Huttenhofer A, Stefanova N (2016) Changes in the miRNA-mRNA regulatory network precede motor symptoms in a mouse model of multiple system atrophy: clinical implications. PLoS ONE 11:e0150705
Scholz SW, Houlden H, Schulte C, Sharma M, Li A, Berg D, Melchers A, Paudel R, Gibbs JR, Simon-Sanchez J, Paisan-Ruiz C, Bras J, Ding J, Chen H, Traynor BJ, Arepalli S, Zonozi RR, Revesz T, Holton J, Wood N, Lees A, Oertel W, Wullner U, Goldwurm S, Pellecchia MT, Illig T, Riess O, Fernandez HH, Rodriguez RL, Okun MS, Poewe W, Wenning GK, Hardy JA, Singleton AB, Del Sorbo F, Schneider S, Bhatia KP, Gasser T (2009) SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 65:610–614
Scholz SW, Majounie E, Revesz T, Holton JL, Okun MS, Houlden H, Singleton AB (2015) Multiple system atrophy is not caused by C9orf72 hexanucleotide repeat expansions. Neurobiol Aging 36(1223):e1221–e1222
Schottlaender LV, Houlden H (2014) Mutant COQ2 in multiple-system atrophy. N Engl J Med 371:81
Schottlaender LV, Holton JL, Houlden H (2014) Multiple system atrophy and repeat expansions in c9orf72. JAMA Neurol 71:1190–1191
Schrag A, Ben-Shlomo Y, Quinn NP (1999) Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study. Lancet 354:1771–1775
Schwarz L, Goldbaum O, Bergmann M, Probst-Cousin S, Richter-Landsberg C (2012) Involvement of macroautophagy in multiple system atrophy and protein aggregate formation in oligodendrocytes. J Mol Neurosci 47:256–266
Seo JH, Yong SW, Song SK, Lee JE, Sohn YH, Lee PH (2010) A case–control study of multiple system atrophy in Korean patients. Mov Disord 25:1953–1959
Shi M, Bradner J, Hancock AM, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Kim HM, Leverenz JB, Montine TJ, Ginghina C, Kang UJ, Cain KC, Wang Y, Aasly J, Goldstein D, Zhang J (2011) Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression. Ann Neurol 69:570–580
Shults CW, Rockenstein E, Crews L, Adame A, Mante M, Larrea G, Hashimoto M, Song D, Iwatsubo T, Tsuboi K, Masliah E (2005) Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. J Neurosci 25:10689–10699
Simonsen AH, Kuiperij B, El-Agnaf OM, Engelborghs S, Herukka SK, Parnetti L, Rektorova I, Vanmechelen E, Kapaki E, Verbeek M, Mollenhauer B (2016) The utility of alpha-synuclein as biofluid marker in neurodegenerative diseases: a systematic review of the literature. Biomark Med 10:19–34
Soma H, Yabe I, Takei A, Fujiki N, Yanagihara T, Sasaki H (2008) Associations between multiple system atrophy and polymorphisms of SLC1A4, SQSTM1, and EIF4EBP1 genes. Mov Disord 23:1161–1167
Sone M, Yoshida M, Hashizume Y, Hishikawa N, Sobue G (2005) alpha-Synuclein-immunoreactive structure formation is enhanced in sympathetic ganglia of patients with multiple system atrophy. Acta Neuropathol 110:19–26
Song YJ, Lundvig DM, Huang Y, Gai WP, Blumbergs PC, Hojrup P, Otzen D, Halliday GM, Jensen PH (2007) p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am J Pathol 171:1291–1303
Spargo E, Papp MI, Lantos PL (1996) Decrease in neuronal density in the cerebral cortex in multiple system atrophy. Eur J Neurol 3:450–456
Spillantini MG, Goedert M (2016) Synucleinopathies: past, present and future. Neuropathol Appl Neurobiol. doi:10.1111/nan.12311 (in print)
Srulijes K, Hauser AK, Guella I, Asselta R, Brockmann K, Schulte C, Solda G, Cilia R, Maetzler W, Schols L, Wenning GK, Poewe W, Barone P, Wullner U, Oertel W, Berg D, Goldwurm S, Gasser T (2013) No association of GBA mutations and multiple system atrophy. Eur J Neurol 20:e61–e62
Starhof C, Korbo L, Funch Lassen C, Winge K, Friis S (2016) Clinical features in a danish population-based cohort of probable multiple system atrophy patients. Neuroepidemiology 46:261–267
Stefanova N, Wenning GK (2015) Animal models of multiple system atrophy. Clin Auton Res 25:9–17
Stefanova N, Wenning GK (2016) Multiple system atrophy: emerging targets for interventional therapies. Neuropathol Appl Neurobiol 42:20–32
Stefanova N, Reindl M, Neumann M, Haass C, Poewe W, Kahle PJ, Wenning GK (2005) Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am J Pathol 166:869–876
Stefanova N, Fellner L, Reindl M, Masliah E, Poewe W, Wenning GK (2011) Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am J Pathol 179:954–963
Stefanova N, Georgievska B, Eriksson H, Poewe W, Wenning GK (2012a) Myeloperoxidase inhibition ameliorates multiple system atrophy-like degeneration in a transgenic mouse model. Neurotox Res 21:393–404
Stefanova N, Kaufmann WA, Humpel C, Poewe W, Wenning GK (2012b) Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. Acta Neuropathol 124:51–65
Stemberger S, Poewe W, Wenning GK, Stefanova N (2010) Targeted overexpression of human alpha-synuclein in oligodendroglia induces lesions linked to MSA-like progressive autonomic failure. Exp Neurol 224:459–464
Sturm E, Stefanova N (2014) Multiple system atrophy: genetic or epigenetic? Exp Neurobiol 23:277–291
Sugiyama A, Ito S, Suichi T, Sakurai T, Mukai H, Yokota H, Yonezu T, Kuwabara S (2015) Putaminal hypointensity on T2*-weighted MR imaging is the most practically useful sign in diagnosing multiple system atrophy: a preliminary study. J Neurol Sci 349:174–178
Sun Z, Xiang X, Tang B, Chen Z, Peng H, Xia K, Jiang H (2015) SNP rs11931074 of the SNCA gene may not be associated with multiple system atrophy in Chinese population. Int J Neurosci 125:612–615
Tanji K, Odagiri S, Maruyama A, Mori F, Kakita A, Takahashi H, Wakabayashi K (2013) Alteration of autophagosomal proteins in the brain of multiple system atrophy. Neurobiol Dis 49:190–198
Teipel S, Drzezga A, Grothe MJ, Barthel H, Chetelat G, Schuff N, Skudlarski P, Cavedo E, Frisoni GB, Hoffmann W, Thyrian JR, Fox C, Minoshima S, Sabri O, Fellgiebel A (2015) Multimodal imaging in Alzheimer’s disease: validity and usefulness for early detection. Lancet Neurol 14:1037–1053
Tong J, Wong H, Guttman M, Ang LC, Forno LS, Shimadzu M, Rajput AH, Muenter MD, Kish SJ, Hornykiewicz O, Furukawa Y (2010) Brain alpha-synuclein accumulation in multiple system atrophy, Parkinson’s disease and progressive supranuclear palsy: a comparative investigation. Brain 133:172–188
Tong J, Ang LC, Williams B, Furukawa Y, Fitzmaurice P, Guttman M, Boileau I, Hornykiewicz O, Kish SJ (2015) Low levels of astroglial markers in Parkinson’s disease: relationship to alpha-synuclein accumulation. Neurobiol Dis 82:243–253
Trojanowski JQ, Growdon JH (1998) A new consensus report on biomarkers for the early antemortem diagnosis of Alzheimer disease: current status, relevance to drug discovery, and recommendations for future research. J Neuropathol Exp Neurol 57:643–644
Trojanowski JQ, Revesz T (2007) Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 33:615–620
Tsuji S (2014) Susceptibility gene in multiple system atrophy (MSA). Rinsho Shinkeigaku 54:969–971
Ubhi K, Lee PH, Adame A, Inglis C, Mante M, Rockenstein E, Stefanova N, Wenning GK, Masliah E (2009) Mitochondrial inhibitor 3-nitropropionic acid enhances oxidative modification of alpha-synuclein in a transgenic mouse model of multiple system atrophy. J Neurosci Res 87:2728–2739
Ubhi K, Rockenstein E, Mante M, Inglis C, Adame A, Patrick C, Masliah E (2010a) Alpha-synuclein deficient mice are resistant to toxin-induced multiple system atrophy. Neuroreport 21:457–462
Ubhi K, Rockenstein E, Mante M, Inglis C, Adame A, Patrick C, Whitney K, Masliah E (2010b) Neurodegeneration in a transgenic mouse model of multiple system atrophy is associated with altered expression of oligodendroglial-derived neurotrophic factors. J Neurosci 30:6236–6246
Ubhi K, Low P, Masliah E (2011) Multiple system atrophy: a clinical and neuropathological perspective. Trends Neurosci 34:581–590
Ubhi K, Rockenstein E, Kragh C, Inglis C, Spencer B, Michael S, Mante M, Adame A, Galasko D, Masliah E (2014) Widespread microRNA dysregulation in multiple system atrophy - disease-related alteration in miR-96. Eur J Neurosci 39:1026–1041
Urbizu A, Canet-Pons J, Munoz-Marmol AM, Aldecoa I, Lopez MT, Compta Y, Alvarez R, Ispierto L, Tolosa E, Ariza A, Beyer K (2015) Cystatin C is differentially involved in multiple system atrophy phenotypes. Neuropathol Appl Neurobiol 41:507–519
Vallelunga A, Ragusa M, Di Mauro S, Iannitti T, Pilleri M, Biundo R, Weis L, Di Pietro C, De Iuliis A, Nicoletti A, Zappia M, Purrello M, Antonini A (2014) Identification of circulating microRNAs for the differential diagnosis of Parkinson’s disease and Multiple System Atrophy. Front Cell Neurosci 8:156
Vanacore N, Bonifati V, Fabbrini G, Colosimo C, De Michele G, Marconi R, Stocchi F, Nicholl D, Bonuccelli U, De Mari M, Vieregge P, Meco G (2005) Case-control study of multiple system atrophy. Mov Disord 20:158–163
VanderHorst VG, Samardzic T, Saper CB, Anderson MP, Nag S, Schneider JA, Bennett DA, Buchman AS (2015) alpha-Synuclein pathology accumulates in sacral spinal visceral sensory pathways. Ann Neurol 78:142–149
Vieira BD, Radford RA, Chung RS, Guillemin GJ, Pountney DL (2015) Neuroinflammation in multiple system atrophy: response to and cause of alpha-synuclein aggregation. Front Cell Neurosci 9:437
Visanji NP, Collingwood JF, Finnegan ME, Tandon A, House E, Hazrati LN (2013) Iron deficiency in parkinsonism: region-specific iron dysregulation in Parkinson’s disease and multiple system atrophy. J Parkinsons Dis 3:523–537
von Bernhardi R, Eugenin-von Bernhardi L, Eugenin J (2015) Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci 7:124
Wakabayashi K, Mori F, Nishie M, Oyama Y, Kurihara A, Yoshimoto M, Kuroda N (2005) An autopsy case of early (“minimal change”) olivopontocerebellar atrophy (multiple system atrophy-cerebellar). Acta Neuropathol 110:185–190
Walsh DM, Selkoe DJ (2016) A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat Rev Neurosci 17:251–260
Watanabe H, Saito Y, Terao S, Ando T, Kachi T, Mukai E, Aiba I, Abe Y, Tamakoshi A, Doyu M, Hirayama M, Sobue G (2002) Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain 125:1070–1083
Watts JC, Giles K, Oehler A, Middleton L, Dexter DT, Gentleman SM, DeArmond SJ, Prusiner SB (2013) Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci USA 110:19555–19560
Wauters SC, Kiely A, Houlden H, Hargreaves I, Holton JL (2016) Mitochondrial dysfunction in multiple system atrophy. Neuropathol Appl Neurobiol 42(suppl 1):37
Wenning GK, Jellinger KA (2005) The role of alpha-synuclein in the pathogenesis of multiple system atrophy. Acta Neuropathol 109:129–140
Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG (2008) Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 64:239–246
Wong JH, Halliday GM, Kim WS (2014) Exploring myelin dysfunction in multiple system atrophy. Exp Neurobiol 23:337–344
Wullner U, Schmitt I, Kammal M, Kretzschmar HA, Neumann M (2009) Definite multiple system atrophy in a German family. J Neurol Neurosurg Psychiatry 80:449–450
Xie T, Kang UJ, Kuo S-H, Poulopoulos M, Greene P, Fahn S (2015) Comparison of clinical features in pathologically confirmed PSP and MSA patients followed at a tertiary center. npj Parkinson’s Dis 1:15007.doi:10.1038/npjparkd.2015.7
Yazawa I, Giasson BI, Sasaki R, Zhang B, Joyce S, Uryu K, Trojanowski JQ, Lee VM (2005) Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45:847–859
Zange L, Noack C, Hahn K, Stenzel W, Lipp A (2015) Phosphorylated alpha-synuclein in skin nerve fibres differentiates Parkinson’s disease from multiple system atrophy. Brain 138:2310–2321
Zhang F, Chen J, Zhao L, Dong C (2014) Candidate biomarkers of multiple system atrophy in cerebrospinal fluid. Rev Neurosci 25:653–662
Acknowledgments
The study was supported in part by the Society for the Promotion of Research in Experimental Neurology, Vienna, Austria. The author thanks Mr. E. Mitter-Ferstl, PhD, for secretarial and computer work.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
None.
Rights and permissions
About this article
Cite this article
Jellinger, K.A., Wenning, G.K. Multiple system atrophy: pathogenic mechanisms and biomarkers. J Neural Transm 123, 555–572 (2016). https://doi.org/10.1007/s00702-016-1545-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-016-1545-2