Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson’s disease
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.
Authors
- Nagendran Ramalingam (ORCID: https://orcid.org/0000-0002-9459-3593)
- Elyse Guadagno
- Jordan Elliott (ORCID: https://orcid.org/0000-0001-8999-570X)
- Fulya Akçimen
- Benjamin N. Sacks (ORCID: https://orcid.org/0000-0003-0143-6589)
- John Hardy (ORCID: https://orcid.org/0000-0002-3122-0423)
- Neha Patel
- Nora Jaber (ORCID: https://orcid.org/0000-0002-1750-4550)
- Ulf Dettmer (ORCID: https://orcid.org/0000-0001-6676-0107)
- Eleanna Kara (ORCID: https://orcid.org/0000-0001-5428-6743)
- Sara Bandrés‐Ciga (ORCID: https://orcid.org/0000-0003-0056-1361)
- Wei Dai (ORCID: https://orcid.org/0000-0003-0169-8327)
- Tim Bartels (ORCID: https://orcid.org/0000-0002-4071-5612)
- Jinying Wang (ORCID: https://orcid.org/0000-0002-5530-4226)
- Ananya Guntur
- M. Maral Mouradian
- Zheng Shi (ORCID: https://orcid.org/0000-0002-5214-1871)
- Jun Liu (ORCID: https://orcid.org/0000-0003-1024-3965)
- Yiming Huang (ORCID: https://orcid.org/0000-0001-5967-557X)
- Elena Eubanks
- Fadel Helweh
- Sanjana Archakam
- Robert Kimelman
- Katelyn VanderSleen
- Philip Socha
- B Sharma
- Jean Baum (ORCID: https://orcid.org/0000-0002-6108-2535)
- Amir Houshang Bahrami
- Jiya Mody
- Mahsa Darestani Farahani
Institutions
- Rutgers, The State University of New Jersey (US)
- National Institutes of Health (US)
- Bilkent University (TR)
- Quantitative BioSciences (US)
- National Institute of Neurological Disorders and Stroke (US)
- National Institute on Aging (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115636
- Citations
- 3
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- National Science Foundation
- Michael J. Fox Foundation for Parkinson's Research
- European Molecular Biology Organization
- Human Frontier Science Program
- National Institutes of Health