Altered α‐synuclein, parkin, and synphilin isoform levels in multiple system atrophy brains

• Published in: Journal of neurochemistry Vol. 136; no. 1; pp. 172 - 185
• Main Authors: Brudek, Tomasz, Winge, Kristian, Rasmussen, Nadja Bredo, Bahl, Justyna Maria Czarna, Tanassi, Julia, Agander, Tina Klitmøller, Hyde, Thomas M., Pakkenberg, Bente
• Format: Journal Article
• Language: English
• Published: England 01.01.2016
• Subjects: Aged; Aged, 80 and over; alpha-Synuclein - biosynthesis; Brain - metabolism; Brain - pathology; Carrier Proteins - biosynthesis; Female; Humans; Male; Middle Aged; multiple system atrophy; Multiple System Atrophy - metabolism; Multiple System Atrophy - pathology; Nerve Tissue Proteins - biosynthesis; parkin; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Protein Isoforms - biosynthesis; synphilin; synucleinopathy; Ubiquitin-Protein Ligases - biosynthesis; α‐synuclein; synucleinopathy; Parkinson's disease; multiple system atrophy; synphilin; parkin; α-synuclein
• DOI: 10.1111/jnc.13392
• ISSN: 0022-3042

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. 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.