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bioRxiv · 10.1101/2021.07.06.451330

GLOBAL EFFECTS OF A PD RISK-SNP AT THE ALPHA-SYNUCLEIN LOCUS

Prahl, J. D.·Pierce, S. E.·van der Schans, E. J.·Coetzee, G. A.·Tyson, T.
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Abstract

SUMMARYOne of the most significant Parkinsons disease (PD) risk variants, rs356182, is located at the PD-associated locus near the alpha-synuclein encoding gene, SNCA. SNCA-proximal variants, including rs356182, are thought to function in PD via allele-specific regulatory effects on SNCA expression. However, this interpretation discounts the complex activity of genetic enhancers and possible nonconical effects of alpha-synuclein. Here we investigate a novel risk mechanism for rs356182. We use CRISPR-Cas9 in LUHMES cells, a model for dopaminergic neurons, to generate precise hemizygous lesions at rs356182. The PD-protective (A/-), PD-risk (G/-), and WT (A/G) strains are differentiated into dopaminergic neurons then compared transcriptionally and morphologically. We observe effects not typically ascribed to SNCA; hundreds of differentially expressed genes associated with neuronal differentiation and axonogenesis. Together, the data implicate a risk mechanism for rs356182 in which the risk-allele (G) is associated with abnormal neuronal differentiation. We speculate the disease-relevant effect originates as a diminished population of DA neurons leading to the predisposition for PD later in life.

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Prahl, J. D., Pierce, S. E., van der Schans, E. J., Coetzee, G. A., Tyson, T.. 2021-07-08. GLOBAL EFFECTS OF A PD RISK-SNP AT THE ALPHA-SYNUCLEIN LOCUS. https://doi.org/10.1101/2021.07.06.451330

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