Evidence map›Paper›PMID 40945514›Full record

ArticleNeuron2025

A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy.

Katherine R Croce, Christopher Ng, Serihy Pankiv, Eddy Albarran, Peter Langfelder, Ana Ramos de Jesus, Glenn M Duncan, Nan Wang, Anna Basile, Caitlin McHugh and 12 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuron, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Review
  3. Macrophage WDFY3, a protector against autoimmunity.bioRxiv : the preprint server for biology · 2024
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors.

Katherine R CroceDoctoral Program in Pathobiology and Mechanism of Disease, Columbia University, New York, NY, USA; Department of Neurology, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
Christopher NgDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Serihy PankivDepartment of Molecular Medicine, University of Oslo, Oslo, Norway.
Eddy AlbarranDepartments of Neurosurgery, Neurology, and Neurological Sciences, Stanford University, Stanford, CA, USA.
Peter LangfelderDepartment of Psychiatry and Biobehavioral Sciences, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Ana Ramos de JesusDepartment of Neurology, Columbia University, New York, NY, USA.
Glenn M DuncanDepartment of Neurology, Columbia University, New York, NY, USA; Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, USA.
Nan WangDepartment of Psychiatry and Biobehavioral Sciences, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Anna BasileNew York Genome Center, New York, NY, USA.
Caitlin McHughNew York Genome Center, New York, NY, USA.
Nicole A LittDepartment of Neurology, Columbia University, New York, NY, USA.
Alina LiDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Sophia FriedmanDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Etty P CortesDepartment of Pathology and Cell Biology, Columbia University, New York, NY, USA; New York Brain Bank, New York, NY, USA.
Michael C ZodyNew York Genome Center, New York, NY, USA.
X William YangDepartment of Psychiatry and Biobehavioral Sciences, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Jun B DingDepartments of Neurosurgery, Neurology, and Neurological Sciences, Stanford University, Stanford, CA, USA.
Jean Paul G VonsattelDepartment of Pathology and Cell Biology, Columbia University, New York, NY, USA; New York Brain Bank, New York, NY, USA.
Anne SimonsenDepartment of Molecular Medicine, University of Oslo, Oslo, Norway.
David E HousmanDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nancy S WexlerDepartment of Neurology, Columbia University, New York, NY, USA; Hereditary Disease Foundation, New York, NY, USA.
Ai YamamotoDepartment of Neurology, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY, USA. Electronic address: ai.yamamoto@columbia.edu.

Funding

The Physical Biology of Neurodegeneration in Sporadic Amyotrophic Lateral Sclerosis/Frontotemporal DementiaR01NS127186 · NINDS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI HOLT, LIAM J, PHATNANI, HEMALI · 2021 to 2025
$8.2M
Project 3: TRiC modulation of CNS pathogenesis in HD mouse modelsP01NS092525 · NINDS · UNIVERSITY OF CALIFORNIA-IRVINE · PI THOMPSON, LESLIE MICHELS · 2016 to 2020
$6.3M
Epigenetic Pathology and Therapy in Huntington's DiseaseR01NS089076 · NINDS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI FRAENKEL, ERNEST, HOUSMAN, DAVID · 2015 to 2024
$4.9M
Modulating selective autophagy to modify Huntington's diseaseR01NS077111 · NINDS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Ai Yamamoto · 2012 to 2026
$4.3M
Dopamine modulation of synaptic plasticity and integration in the striatumR01NS091144 · NINDS · STANFORD UNIVERSITY · PI Jun Ding · 2015 to 2026
$4.2M
Novel mouse genetic models to study modifiers of Huntington’s diseaseR01NS113612 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI YANG, XIANGDONG WILLIAM · 2019 to 2023
$3.2M
Selective autophagy in Parkinson'sdiseaseR01NS101663 · NINDS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Ai Yamamoto · 2018 to 2026
$3.1M
Dopamine Degradation Pathway and Alpha-synuclein AggregationR01NS103037 · NINDS · STANFORD UNIVERSITY · PI DING, JUN · 2017 to 2021
$1.9M
Calcium signaling and autophagy defects in Alzheimer's disease neuronsR01AG090542 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Ai Yamamoto · 2025 to 2026
$1.5M
NIA NIH HHS R01 AG090542NINDS NIH HHS P01 NS092525NINDS NIH HHS R01 NS077111NINDS NIH HHS R01 NS089076NINDS NIH HHS R01 NS091144NINDS NIH HHS R01 NS101663NINDS NIH HHS R01 NS103037NINDS NIH HHS R01 NS113612NINDS NIH HHS R01 NS127186
6 · The paper itself

Abstract

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.

Indexed as

AutophagyHuntington DiseaseNeurodegenerative DiseasesPolymorphism, Single NucleotideAnimalsDisease Models, AnimalHumansMaleMiceMice, TransgenicautophagyHuntington’s diseaseneurodegenerationParkinson’s diseaseproteinopathyselective autophagysynucleintauopathyWDFY3/Alfy

Identifiers

PMID40945514
PMCPMC12435916

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.