Huntington’s Disease

What goes wrong in Huntington's

Huntington's disease is rare among neurodegenerative diseases in having a single, well-defined cause. Everyone who inherits the mutation will develop the disease — usually in mid-life — and the gene responsible has been known for decades.

That mutation is a CAG repeat expansion in the HTT gene. CAG is the genetic code for glutamine, so a long stretch of CAG repeats produces a protein, called huntingtin, with an unusually long run of glutamines — a "poly-Q tract." Up to about 35 glutamines is fine. Past that threshold, huntingtin starts misfolding and sticking to other copies of itself. The longer the tract, the earlier the disease appears.

The misfolded copies pile up inside neurons and slowly poison them. The cells of the striatum, the brain region that coordinates movement, are hit hardest — which is why the disease's most visible symptoms are involuntary movements alongside cognitive decline.

What Folding@home is doing

Because every case of Huntington's is driven by the same kind of misfolding, blocking that misfolding could in principle stop the disease before it starts. The hard part is that the early stages of poly-Q aggregation are difficult to study — the toxic species are short-lived, structurally variable, and form too quickly for experiments to catch.

Folding@home runs the kinds of simulations needed to map those early steps. Donated compute lets us track how an expanded huntingtin finds other copies of itself and locks into aggregates — and then identify the molecular handholds where a small molecule could disrupt the process.

Every CPU and GPU joining Folding@home advances those simulations. It's the kind of slow, parallel, decade-long work that only a volunteer network of this scale can sustain.

Folding@home on Huntington's