Huntington's Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy

Neuron. 2020 Mar 4;105(5):813-821.e6. doi: 10.1016/j.neuron.2019.12.003. Epub 2019 Dec 30.


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.

Keywords: Alfy; Huntington's disease; Wdfy3; autophagy; direct conversion; mice; neurodegeneration; patient fibroblasts; proteinopathy; selective autophagy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Age of Onset
  • Animals
  • Autophagy-Related Proteins / genetics*
  • Cell Death / genetics
  • Disease Models, Animal
  • Female
  • Fibroblasts
  • Humans
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Huntington Disease / physiopathology
  • Macroautophagy / genetics*
  • Male
  • Mice
  • Mice, Knockout
  • Neurons / metabolism*
  • Protein Aggregation, Pathological / genetics*
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / physiopathology


  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Huntingtin Protein
  • WDFY3 protein, human
  • Wdfy3 protein, mouse