Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson’s disease DOI Creative Commons

Elena Eubanks,

Katelyn VanderSleen,

Jiya Mody

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(5), P. 115636 - 115636

Published: May 1, 2025

Alpha-synuclein (αSyn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson's disease (PD). Through a high-throughput screen, we recently identified 38 genes whose knockdown modulates αSyn propagation. Here, show that, among those, TAX1BP1 regulates how interacts lipids, and ADAMTS19 phase separates into inclusions, adding to growing body evidence implicating those processes PD. RNA sequencing, identify several are differentially expressed after or carry increased frequency rare risk variants PD versus healthy controls. Those cluster within modules regions brain develop high degrees pathology. We propose model for genetic architecture sporadic PD: burden across networks dysregulates pathways underlying homeostasis leads pathology neurodegeneration.

Language: Английский

Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson’s disease DOI Creative Commons

Elena Eubanks,

Katelyn VanderSleen,

Jiya Mody

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(5), P. 115636 - 115636

Published: May 1, 2025

Alpha-synuclein (αSyn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson's disease (PD). Through a high-throughput screen, we recently identified 38 genes whose knockdown modulates αSyn propagation. Here, show that, among those, TAX1BP1 regulates how interacts lipids, and ADAMTS19 phase separates into inclusions, adding to growing body evidence implicating those processes PD. RNA sequencing, identify several are differentially expressed after or carry increased frequency rare risk variants PD versus healthy controls. Those cluster within modules regions brain develop high degrees pathology. We propose model for genetic architecture sporadic PD: burden across networks dysregulates pathways underlying homeostasis leads pathology neurodegeneration.

Language: Английский

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