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TitleIncreased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease.
Journal, issue, pagesCell Rep, Vol. 44, Issue 5, Page 115636, Year 2025
Publish dateMay 27, 2025
AuthorsElena Eubanks / Katelyn VanderSleen / Jiya Mody / Neha Patel / Benjamin Sacks / Mahsa Darestani Farahani / Jinying Wang / Jordan Elliott / Nora Jaber / Fulya Akçimen / Sara Bandres-Ciga / Fadel Helweh / Jun Liu / Sanjana Archakam / Robert Kimelman / Bineet Sharma / Philip Socha / Ananya Guntur / Yiming Huang / Nagendran Ramalingam / Elyse Guadagno / Tim Bartels / Ulf Dettmer / M Maral Mouradian / Amir Houshang Bahrami / Wei Dai / Jean Baum / Zheng Shi / John Hardy / Eleanna Kara /
PubMed AbstractAlpha-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 ...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, we show that, among those, TAX1BP1 regulates how αSyn interacts with lipids, and ADAMTS19 modulates how αSyn phase separates into inclusions, adding to the growing body of evidence implicating those processes in PD. Through RNA sequencing, we identify several genes that are differentially expressed after knockdown of TAX1BP1 or ADAMTS19 and carry an increased frequency of rare risk variants in patients with PD versus healthy controls. Those differentially expressed genes cluster within modules in regions of the brain that develop high degrees of αSyn pathology. We propose a model for the genetic architecture of sporadic PD: increased burden of risk variants across genetic networks dysregulates pathways underlying αSyn homeostasis and leads to pathology and neurodegeneration.
External linksCell Rep / PubMed:40317721 / PubMed Central
MethodsEM (tomography)
Structure data

EMDB-46757: Cryo-electron tomography of amorphous alpha-synuclein aggregates with embedded membranes and a lipid droplet
Method: EM (tomography)

EMDB-46764: Mitochondrial membrane with external amorphous alpha-synuclein aggregate
Method: EM (tomography)

Source
  • Homo sapiens (human)

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