title: Altered α-synuclein, parkin, and synphilin isoform levels in multiple system atrophy brains.
abstract: Together with Parkinson's disease (PD) and dementia with Lewy bodies, multiple system atrophy (MSA) is a member of a diverse group of neurodegenerative disorders termed α-synucleinopathies. Previously, it has been shown that α-synuclein, parkin, and synphilin-1 display disease-specific transcription patterns in frontal cortex in PD, dementia with Lewy bodies, and MSA, and thus may mediate the development of α-synucleinopathies. In this study, the differential expression of α-synuclein isoforms on transcriptional and translational levels was ascertained in MSA patients in comparison with PD cases and normal controls using isoform-specific primers and exon-specific antibodies in substantia nigra, striatum, cerebellar cortex, and nucleus dentatus. These regions are severely affected by α-synuclein pathology and neurodegeneration. Furthermore, we have also investigated transcript levels for parkin and synphilin-1 isoforms. In MSA brains, α-synuclein140 and α-synuclein 112 isoform levels were significantly increased, whereas levels of the α-synuclein 126 isoform were decreased in the substantia nigra, striatum, cerebellar cortex, and nucleus dentatus versus controls. Moreover, in MSA cases, we showed increased levels of parkin isoforms lacking the N-terminal ubiquitin-like domain and an aggregation-prone synphilin-1A isoform that causes neuronal toxicity in MSA. In PD brains, parkin transcript variant 3, 7, and 11 were significantly and specifically over-expressed in the striatum and cerebellar cortex, together with synphilin-1A and 1C. The changes of isoform expression profiles in neurodegenerative diseases suggest alterations in the regulation of transcription and/or splicing events, leading to regional/cellular events that may be important for the highly increased aggregation of α-synuclein in the brain. We report differential expression of α-synuclein, parkin, and synphilin-1 isoforms in multiple system atrophy (MSA) versus Parkinson's disease and normal control brains. We have focused on brain regions that are severely affected by α-synuclein pathology and neurodegeneration in MSA. The reported changes of isoform expression profiles suggest alterations in the regulation of transcription that may be important for aggregation of α-synuclein in the brain.
authors.affiliation: Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen NV, Denmark.|Bispebjerg Movement Disorders Biobank, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen N, Denmark.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Brudek
authors.affiliation: Department of Neurology, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen NV, Denmark.|Bispebjerg Movement Disorders Biobank, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen N, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Winge
authors.affiliation: Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen NV, Denmark.
authors.forename: Nadja Bredo
authors.initials: NB
authors.lastname: Rasmussen
authors.affiliation: Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen S, Denmark.
authors.forename: Justyna Maria Czarna
authors.initials: JM
authors.lastname: Bahl
authors.affiliation: Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen S, Denmark.
authors.forename: Julia
authors.initials: J
authors.lastname: Tanassi
authors.affiliation: Department of Pathology, Rigshospitalet University Hospital, Copenhagen, Denmark.
authors.forename: Tina Klitmøller
authors.initials: TK
authors.lastname: Agander
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen NV, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Pakkenberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000096:biosynthesis; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*; D051844:alpha-Synuclein / Q000096:biosynthesis*
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C118958:SNCAIP protein, human; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: Parkinson's disease; multiple system atrophy; parkin; synphilin; synucleinopathy; α-synuclein