Altered [alpha]-synuclein, parkin, and synphilin isoform levels in multiple system atrophy brains

• Published in: Journal of neurochemistry 2016-01, Vol.136 (1), p.172
• Main Authors: Brudek, Tomasz, Winge, Kristian, Rasmussen, Nadja Bredo, Bahl, Justyna Maria Czarna, Tanassi, Julia, Agander, Tina Klitmøller, Hyde, Thomas M, Pakkenberg, Bente
• Format: Article
• Language: English
• Subjects: Brain; Neurodegeneration; Parkinson's disease
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.13392

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 [alpha]-synucleinopathies. Previously, it has been shown that [alpha]-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 [alpha]-synucleinopathies. In this study, the differential expression of [alpha]-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 [alpha]-synuclein pathology and neurodegeneration. Furthermore, we have also investigated transcript levels for parkin and synphilin-1 isoforms. In MSA brains, [alpha]-synuclein140 and [alpha]-synuclein 112 isoform levels were significantly increased, whereas levels of the [alpha]-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 [alpha]-synuclein in the brain. We report differential expression of [alpha]-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 [alpha]-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 [alpha]-synuclein in the brain.