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.
Alpha-synuclein, a main component of Lewy bodies in synucleinopathies and senile plaques in Alzheimer disease, is centrally involved in neurodegeneration. Three different isoforms (alpha-synuclein 112, 126, and 140) resulting from alternative splicing have been described so far. The present study explores alpha-synuclein 126 mRNA expression levels in the prefrontal cortex of six patients with dementia with Lewy bodies, eight patients with Lewy body variant of Alzheimer disease, eight patients with Alzheimer disease, and 10 controls. Relative alpha-synuclein 126 expression levels were determined by real-time polymerase chain reaction with competimer technology. Alpha-synuclein 126 mRNA expression was markedly decreased in the three dementias in comparison with controls, suggesting an important role of this alpha-synuclein isoform in the normal brain.
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