The effect of SNCA 3′ region on the levels of SNCA-112 splicing variant
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Genetic variability at the 3′ region of SNCA locus has been repeatedly associated with susceptibility to sporadic Parkinson’s disease (PD). Accumulated evidence emphasizes the importance of SNCA dosage and expression levels in PD pathogenesis. However, the mechanism through which the 3′ region of SNCA gene modulates the risk to develop sporadic PD remained elusive. We studied the effect of PD risk-associated variants at SNCA 3′ regions on SNCA112-mRNA (exon 5 in-frame skipping) levels in vivo in 117 neuropathologically normal, human brain frontal cortex samples. SNPs tagging the SNCA 3′ showed significant effects on the relative levels of SNCA112-mRNA from total SNCA transcripts levels. The “risk” alleles were correlated with increased expression ratio of SNCA112-mRNA from total. We provide evidence for functional consequences of PD-associated SNCA gene variants at the 3′ region, suggesting that genetic regulation of SNCA splicing plays an important role in the development of the disease. Further studies to determine the definite functional variant/s within SNCA 3′and to establish their association with PD pathology are necessary.
KeywordsSNCA-mRNA SNCA112 Splicing Parkinson’s disease Functional variants eSNP
This work was supported in part by the Ellison Medical Foundation New Scholar award AG-NS-0441-08 (O.C.) and the Institute for Genome Sciences and Policy at Duke University (O.C.). We thank the Kathleen Price Bryan Brain Bank (KPBBB) at Duke University funded by NIA AG028377, the National NeuroAIDS Tissue Consortium (NNTC), Layton Aging & Alzheimer’s Disease Center at Oregon Health and Science University funded by NIA AG008017, and the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore (NICHD contract no. HHSN275200900011C, Ref. No. NO1-HD-9-0011), for providing us with the brain tissues. We would also like to thank Dr. Randy Woltjer, Dr. Kathleen Hayden, Dr. Lauren Warren, Mari Szymanski, and John Ervin for their assistance in obtaining the required brain samples for the study.
The experiments comply with the current laws of the USA.
Conflict of interest
The authors declare that they have no conflict of interest.