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

A rare single-nucleotide polymorphism in WDFY3 is associated with a delayed age of onset of up to 23 years for Huntington's disease.

• The introduction of the orthologous SNP into mice significantly delays neuropathological and behavioral dysfunction in Huntington's disease models.
• This SNP increases the expression of the autophagy adaptor protein Alfy, which helps clear aggregated proteins.
• Ectopic overexpression of Alfy can replicate the neuroprotective effects of the SNP.
• Increasing Alfy expression shows protective effects not only against Huntington's disease but also against toxicity from phospho-α-synuclein and AT8-positive accumulation.
• The findings suggest a shared therapeutic target for multiple neurodegenerative diseases through the identified pathway.

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