Genetic variant delays Huntington’s onset by up to 23 years: Study
Data from patients, mouse models suggests it protects against multiple diseases
In a large Venezuelan family with Huntington’s disease, members with a rare variant in the WDFY3 gene developed symptoms up to 23 years later than expected, a study showed.
The WDFY3 gene encodes Alfy, a protein that helps clear protein clumps, such as those driving Huntington’s and other proteinopathies — an umbrella term for diseases marked by a buildup of misfolded proteins.
Data from patients and mouse models suggested that the genetic variant protects against multiple neurodegenerative proteinopathies.
“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,” researchers wrote.
The study, “A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy,” was published in the journal Neuron.
Members of Venezuelan family see delay in symptom onset of 6 to 23 years
In Huntington’s, excessive repeats of a DNA sequence in the HTT gene cause the huntingtin protein to build up as toxic clumps that gradually damage nerve cells in the brain. This leads to problems with movement, cognition, and behavior that usually begin in mid-adulthood.
A larger number of repeats is associated with an earlier age at symptom onset. However, not all people with the same number of repeats develop symptoms at the same age, suggesting that other genetic factors, known as genetic modifiers, can influence onset.
In this study, a team of researchers in the U.S. identified a genetic variant in the WDFY3 gene that delayed the onset of Huntington’s by 6 to 23 years in a Venezuelan family. The rare variant, reported in up to 1% of the general population, is a single-nucleotide polymorphism (SNP), meaning it replaces just one building block in the DNA sequence.
The WDFY3 gene provides the instructions to produce Alfy, a protein that has been shown to be key for clearing toxic huntingtin clumps in a mouse model of Huntington’s.
Variant associated with fewer protein clumps
To test if this SNP protected against Huntington’s, the researchers inserted the same genetic variant in a Huntington’s mouse model, which develops symptoms similar to those in patients. However, Huntington’s mice carrying the genetic variant showed similar motor function and behavior as healthy mice.
The SNP was also associated with fewer protein clumps. Further experiments showed that this protective effect stemmed from the SNP stabilizing the WDFY3 gene’s messenger RNA (mRNA), the intermediate molecule derived from DNA that serves as a guide for protein production.
Normally, mRNA can degrade quickly, but the SNP made it more stable, allowing cells to produce higher amounts of the Alfy protein. This means more toxic clumps could be cleared before they damaged nerve cells.
Similar protective effects were observed when the team modified the Huntington’s mouse model to overproduce Alfy.
By leveraging the strengths of human and mouse genetics, we identified a potent modifier of neurodegenerative diseases that evokes protection by preventing protein accumulation, providing critical insight into the relevance of diminishing protein-mediated toxicity and positive outcomes in the adult brain.
Importantly, the benefit of Alfy was not limited to Huntington’s. Boosting Alfy production in mouse models of Parkinson’s disease and Alzheimer’s disease, both of which are neurodegenerative proteinopathies, reduced the buildup of misfolded proteins and delayed neurodegeneration.
“By leveraging the strengths of human and mouse genetics, we identified a potent modifier of neurodegenerative diseases that evokes protection by preventing protein accumulation, providing critical insight into the relevance of diminishing protein-mediated toxicity and positive outcomes in the adult brain,” the researchers wrote.
These findings suggest that increasing Alfy levels could be a common strategy for many neurodegenerative diseases that currently have limited treatment options.
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