A Tiny Genetic Tweak Could Delay Symptoms and Activate Cellular Cleanup for Huntington’s Disease

Scientists often use genetics, the study of DNA, to understand the cellular changes that cause disease. By comparing people’s DNA with their symptoms, they can pinpoint specific genetic differences, called variants, that influence the severity of a disease. Huntington’s disease (HD) is well-suited for genetic analysis because of its well-understood genetic roots – an expansion mutation in the HTT gene. In HD, the genetic letters CAG repeat too many times, and this repetition leads to the disease. Since this discovery, scientists have searched the entire genetic makeup of tens of thousands of people for variants that modify when HD starts, called the age of onset. Defining these variants and testing their therapeutic potential could lead to the development of drugs that delay when HD signs and symptoms appear. 

Genetic Patterns

Unlike most brain diseases, HD offers a unique opportunity for genetic analysis because a simple blood test can determine if someone will develop the disease, and its timing is somewhat predictable. As an example, someone with 42 CAGs might start to show symptoms in their 40s or 50s, but someone with over 100 CAGs is likely to show symptoms as a child. Because the onset of symptoms is correlated to the length of a person’s CAG expansion, scientists can comb for additional genetic variations that change the expected age of onset. 

For example, while someone may or may not get Alzheimer’s Disease, people with the HD mutation are certain to develop the disease if they live long enough, and this predictability means scientists can look for variants that delay or prevent the expected age of onset. These predictions aren’t perfect (usually within ~10 years), but when combined with large groups of people, these techniques can identify genetic variations that affect disease timing. This is a powerful approach for identifying potential therapeutic targets. 

In a new study, work spearheaded by Dr. Katherine Croce from the lab of Dr. Ai Yamamoto at Columbia University took advantage of HD’s predictability to search for people whose expected age of onset did not match their actual age of onset. By comparing a person’s age of onset to their DNA, they found a tiny genetic variant in a gene called WDFY3 that appeared to delay the onset of HD by between 6 to 23 years – potentially a massive amount! 

However, this effect was only observed in a single HD family. (Albeit a very large HD family from Venezuela.) In addition, this genetic quirk is only found in around 1% of the population, and HD is already a rare disease, so confirming this effect in other HD families could be difficult. 

Cleanup on Aisle Brain

Without more human data to confirm WDFY3’s protective effect, the researchers turned to animal models. By introducing the same WDFY3 variant into a mouse that models HD, the researchers investigated whether they could recreate the protective effect. Remarkably, changing just a single genetic letter in the WDFY3 gene reduced neuron loss in the striatum, the vulnerable brain region in HD, and also lowered various stress signals associated with disease, such as the buildup of toxic protein clumps. These protein clumps form because the expanded HTT protein doesn’t fold correctly, causing it to pile up in large garbage deposits that promote neuron death.

The team next asked how this tiny genetic change in WDFY3 could have such a huge impact. To find out, they looked at the protein made by WDFY3, called ALFY, which carries out the gene’s function in the cell. Genes like WDFY3 are the blueprints for protein machines, like ALFY, that perform various activities in the cell. 

Surprisingly, the genetic variation in WDFY3 was not affecting the activity of ALFY, but was instead boosting the amount of ALFY floating around in the cell. When the researchers artificially increased the amount of ALFY in cells without the protective variant, they still observed a similar protective effect. These results suggest that the WDFY3 variant protects neurons not by changing what ALFY does, but by simply increasing how much of it is produced. So what is ALFY doing, and why does having more of it help keep neurons healthy?

Boosting the Brain’s Clean Up Crew

Previous research has shown that ALFY helps tag old misfolded proteins for removal. ALFY is like a custodian sticking bright orange stickers on old equipment that needs to be hauled away for disposal. By marking these piles of protein garbage, the cleanup crew knows what to haul away. 

Based on ALFY’s known function, the researchers thought that higher ALFY levels simply improve the efficiency of the cell’s cleanup systems. If this were true, then raising ALFY levels should protect against toxic proteins building up in other brain diseases, like Parkinson’s Disease or Alzheimer’s Disease. These diseases, like HD, have a major problem with protein garbage piles building up. And sure enough, they found that higher levels of ALFY seemed to protect neurons in mice that model these brain diseases as well, suggesting a common pathway was at work. 

Collectively, these experiments show that a tiny genetic change in WDFY3, which may delay the onset of symptoms in HD, likely works by boosting the production of its protein product ALFY. Like hiring extra custodians, more ALFY helps keep neurons tidy by clearing away the toxic misfolded proteins that accumulate in HD and contribute to damage in neurons. These results are doubly exciting because other brain diseases like Parkinson’s Disease and Alzheimer’s Disease face similar problems and could equally benefit from having more ALFY around. 

Therapeutic drugs aimed at boosting ALFY could mimic the protection seen in people with the original WDFY3 variant the researchers identified. Although no such drugs currently exist, the idea of improving the brain’s cellular cleanup crew could offer promise for multiple brain diseases, not just HD. If treatments to safely boost ALFY can be discovered, they may unlock a way to slow or prevent the protein buildup that contributes to brain cell breakdown in not just HD, but other brain diseases as well. 

Summary

• Huntington’s disease (HD) is uniquely suited for genetic studies because CAG length predicts (roughly) when symptoms will start.
• Researchers searched for people whose actual age of onset didn’t match their predicted onset to find genetic modifiers.
• A rare variant in WDFY3 was found in one large Venezuelan HD family and may delay onset by 6–23 years.
• The variant boosts levels of the WDFY3 protein ALFY, which helps cells clear misfolded protein “garbage.”
• In mice that model HD, increasing ALFY reduced neuron loss and toxic protein buildup, even without the protective genetic variant.
• Raising ALFY also protected neurons in mouse models of Parkinson’s and Alzheimer’s, suggesting a shared protective pathway.
• No ALFY-boosting drugs exist yet, but targeting this cleanup system could become a promising treatment strategy for HD and other brain diseases.

Learn More

Original research article, “A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy” (open access).