A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy
The study of disease modifiers is a powerful way to identify patho-mechanisms associated with disease. Using the strong genetic traits of Huntington's disease (HD), we identified a rare, single-nucleotide polymorphism (SNP) in WDFY3 associated with a delayed age of onset of up to 23 years. Remarkably, the introduction of the orthologous SNP into mice recapitulates this neuroprotection, significantly delaying neuropathological and behavioral dysfunction in two models of HD. The SNP increases expression of the protein autophagy-linked Fab1, YOTB, Vac1, and EEA1 (FYVE) protein (Alfy), an autophagy adaptor protein for the clearance of aggregated proteins, whose ectopic overexpression is sufficient to capture the neuroprotective effects of the variant. Increasing Alfy expression protects not only against HD but also against the toxicity due to phospho-α-synuclein and AT8-positive accumulation. By combining human and mouse genetics, we have uncovered a pathway that protects against multiple proteinopathies, revealing a much-sought-after, shared therapeutic target across a broad range of neurodegenerative diseases.
Authors
- Nicole A. Litt
- Alina Li
- Peter Langfelder (ORCID: https://orcid.org/0000-0003-3418-4146)
- Etty Cortés (ORCID: https://orcid.org/0000-0002-5221-8963)
- Anna O. Basile (ORCID: https://orcid.org/0000-0001-5112-5880)
- Nancy S. Wexler (ORCID: https://orcid.org/0000-0002-4591-0943)
- Michael C. Zody (ORCID: https://orcid.org/0000-0001-6594-7199)
- Katherine R. Croce
- Christopher Ng (ORCID: https://orcid.org/0000-0001-8815-7958)
- Eddy Albarran (ORCID: https://orcid.org/0000-0002-1638-100X)
- Serhiy Pankiv (ORCID: https://orcid.org/0000-0001-7953-2445)
- Ai Yamamoto (ORCID: https://orcid.org/0000-0002-7059-2449)
- Jun Ding (ORCID: https://orcid.org/0000-0003-0690-1312)
- Anne Simonsen (ORCID: https://orcid.org/0000-0003-4711-7057)
- Gary H. Duncan (ORCID: https://orcid.org/0000-0002-0498-433X)
- Ângelo Jesus (ORCID: https://orcid.org/0000-0003-3972-8253)
- Xia Yang (ORCID: https://orcid.org/0000-0002-3971-038X)
- Nan Wang (ORCID: https://orcid.org/0000-0003-4263-5074)
- Caitlin P. McHugh (ORCID: https://orcid.org/0000-0001-8913-2058)
- David E. Housman (ORCID: https://orcid.org/0000-0001-5016-0756)
- Sy D. Friedman
- Jean Paul Vonsattel
Institutions
- University of Oslo (NO)
- Neurobehavioral Systems (US)
- New York Genome Center (US)
- Massachusetts Institute of Technology (US)
- Columbia University (US)
- Stanford University (US)
Publication Details
- Journal
- Neuron
- Published
- 2025-09-13
- DOI
- https://doi.org/10.1016/j.neuron.2025.08.018
- Citations
- 5
- Primary Topic
- Neurological diseases and metabolism
- Type
- article
- Field-Weighted Citation Impact
- 3.37