English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

One of the most significant risk variants for Parkinson’s disease (PD), rs356182, is located at the PD-associated locus near the alpha-synuclein (α-syn) encoding gene,  SNCA .  SNCA -proximal variants, including rs356182, are thought to function in PD risk through enhancers via allele-specific regulatory effects on  SNCA  expression. However, this interpretation discounts the complex activity of genetic enhancers and possible non-conical functions of α-syn. Here we investigated a novel risk mechanism for rs356182. We use CRISPR-Cas9 in LUHMES cells, a model for dopaminergic midbrain neurons, to generate precise hemizygous lesions at rs356182. The PD-protective (A/−), PD-risk (G/−) and wild-type (A/G) clones were neuronally differentiated and then compared transcriptionally and morphologically. Among the affected genes was  SNCA , whose expression was promoted by the PD-protective allele (A) and repressed in its absence. In addition to  SNCA , hundreds of genes were differentially expressed and associated with neurogenesis and axonogenesis—an effect not typically ascribed to α-syn. We also found that the transcription factor FOXO3 specifically binds to the rs356182 A-allele in differentiated LUHMES cells. Finally, we compared the results from the rs356182-edited cells to our previously published knockouts of  SNCA  and found only minimal overlap between the sets of significant differentially expressed genes. Together, the data implicate a risk mechanism for rs356182 in which the risk-allele (G) is associated with abnormal neuron development, independent of  SNCA  expression. We speculate that these pathological effects manifest as a diminished population of dopaminergic neurons during development leading to the predisposition for PD later in life.

The Parkinson’s disease variant rs356182 regulates neuronal differentiation independently from alpha-synuclein