Huntington’s Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy
Open accessAbstract
Despite being an autosomal dominant disorder caused by a known coding mutation in the gene HTT, Huntington's disease (HD) patients with similar trinucleotide repeat mutations can have an age of onset that varies by decades. One likely contributing factor is the genetic heterogeneity of patients that might modify their vulnerability to disease. We report that although the heterozygous depletion of the autophagy adaptor protein Alfy/Wdfy3 has no consequence in control mice, it significantly accelerates age of onset and progression of HD pathogenesis. Alfy is required in the adult brain for the autophagy-dependent clearance of proteinaceous deposits, and its depletion in mice and neurons derived from patient fibroblasts accelerates the aberrant accumulation of this pathological hallmark shared across adult-onset neurodegenerative diseases. These findings indicate that selectively compromising the ability to eliminate aggregated proteins is a pathogenic driver, and the selective elimination of aggregates may confer disease resistance.
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Defective autophagy imposed by heterozygous depletion of the autophagy scaffold/adaptor WDFY3/ALFY accelerates the onset (and worsens the sequelae) of HD in mice.
“Of note, defective autophagy imposed by heterozygous depletion of the autophagy scaffold/adaptor WDFY3/ALFY (WD repeat and FYVE domain containing 3) accelerates the onset (and worsens the sequelae) of HD in mice (Fox et al, 2020).”
From Autophagy in major human diseases (2021) · cites this paper as Fox et al, 2020
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- Authors
- Fox, L. M., Kim, K., Johnson, C. W., Chen, S., Croce, K. R., Victor, M. B., Eenjes, E., Bosco, J. R., Randolph, L. K., Dragatsis, I., Dragich, J. M., Yoo, A. S., & Yamamoto, A.
- Affiliations
- Columbia University (US)
- Washington University in St. Louis (US)
- Corresponding author
- Yamamoto, Ai
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 105
- Issue
- 5
- Pages
- 813-821.e6
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC7060123
- OpenAlex
- W2997080716
- Cited by
- 76
- References
- 47
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 12 · 2023: 11 · 2022: 16 · 2021: 10 · 2020: 6
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Hereditary Disease Foundation
- Huntington's Disease Society of America
- National Institute of Neurological Disorders and Stroke
- National Science Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Huntington's disease, autophagy, age of onset, protein aggregation, neurodegeneration, disease resistance, protein clearance
- MeSH terms
- Huntingtin Protein, Autophagy-Related Proteins, Macroautophagy, Animals, Disease Models, Animal, Female, Fibroblasts, Humans, Huntington Disease, Male, Neurons, Cell Death, Age of Onset, Mice, Knockout, Adaptor Proteins, Signal Transducing, Mice, Protein Aggregation, Pathological
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