Differential expression of alpha-synuclein, parkin, and synphilin-1 isoforms in Lewy body disease

Abstract

Alpha-synuclein, parkin, and synphilin-1 are proteins mainly involved in the pathogenesis of Lewy body (LB) diseases. mRNAs of all three undergo alternative splicing, so that the existence of various isoforms has been described. Since increasing evidence supports the importance of differential isoform-expression changes in disease development, we have established isoform-expression profiles in frontal cortices of LB disease brains in comparison with those of Alzheimer disease (AD) and control frontal cortices. The differential expression of four alpha-synuclein, seven parkin, and four synphilin-1 isoforms was ascertained by the use of isoform-specific primers and relative expression analysis with SybrGreen and beta-actin as an internal standard. The establishment of isoform-expression profiles revealed that these are disease specific. Moreover, isoform-expression deregulation of mainly one gene in each disease could be observed. All four alpha-synuclein isoforms were affected in the case of the pure form of dementia with LB, most parkin transcript variants in common LB disease, and all synphilin-1 isoforms in Parkinson disease. Only minor involvement was detected in AD. Finally, the existence of a proprietary isoform-expression profile in common LB disease indicates that this disease develops as a result of its own molecular mechanisms, and so, at the molecular level, it does not exactly share changes found in pure dementia with LB and AD. In conclusion, isoform-expression profiles in LB diseases represent additional evidence for the direct involvement of isoform-expression deregulation in the development of neurodegenerative disorders.

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

“…Full-length α-syn (α-synFL) contains seven exons (20). [Note: Exon numbering has been adjusted recently, because of the discovery of a new exon (21).] Exons one and two, and part of exon three, constitute the 5′ UTR of the mRNA.…”

“…Both exon four and exon six are subject to alternative splicing, creating α-synΔ4 and α-synΔ6, respectively. These variants are differentially expressed in various synucleinopathies (20,21), and recent work has tied PD risk factors to increased splicing of exon six (22,23). However, it is not clear whether this change in splicing contributes to pathology, is part of a protective mechanism, or is functionally inconsequential.…”

Localization of Synucleins in the Mammalian Cochlea

“…(Beyer et al 2008;Fuchs et al 2008;Muller et al 2005) It is thus intriguing to speculate that a similar phenomenon may be occurring in degenerative auditory processes. While synuclein isoforms were not specifically sought in this work, it would certainly be worthy of further investigation.…”

A structured sparse regression method for estimating isoform expression level from multi-sample RNA-seq data

“…Changes in isoform expression levels of alternatively spliced genes are of functional importance in particular biological processes. For example, there is much evidence that the development of many complex diseases is highly correlated with changes in isoform expression levels (Humbert et al, 2007;Beyer et al, 2008). Therefore, accurately estimating isoform expression levels remains an important challenge for understanding complicated biological mechanisms.…”