Time travel inside Huntington's brain

Happy Friday! One of the talks at the ASHG 2023 blew the minds of the audience. It was a talk on single cell sequencing of brain tissue from Huntington's patients, presented by Bob Handsaker from Steve McCarroll's group at the Broad Institute in Boston. I didn't grab the whole story during the presentation. But the parts that I heard and the final revised disease model that Bob presented felt groundbreaking, and I couldn't contain my excitement. I tweeted about it that night, and many agreed with what I felt. I spoke about it with Patrick Short (who was as excited as I was about this work) in the 2023 year-end episode of The Genetics Podcast. However, I feared that I may have overblown the impact of the work prematurely, and the balloon would burst someday when the actual preprint comes out. Like many others, I've been waiting for the preprint to drop.

Steve's team finally posted their work in the medRxiv a week ago. Having now read the paper fully, I can say with full confidence that the hype that Bob's ASHG presentation received is well deserved. The work described in the preprint is as just as impressive as I imagined. The work has already garnered a lot of excitement in the community. Here is a tweet from Mark Daly, a reputed, world famous scientist in human genetics. I don’t remember hearing such a praise from Mark on any work before.

What’s known?

It's important we first understand what's already known to appreciate what's new. Huntington's disease is caused by expansion of a microsatellite mutation--CAG repeat--located in the exon 1 of HTT gene in chromosome 4. The number of CAG repeats in the general population range between 15-30, whereas in Huntington's patients it is between 36 and 55.

The CAG repeats in the HTT gene transcribe and translate into poly-glutamine chain in the Huntingtin protein; the HTT is expressed in the fetal and adult brain, among other tissues. The huntingtin protein with an elongated poly-glutamine tract is neurotoxic. It erodes the neurons, particularly the neurons of the striatum, over time in the Huntington's patients, resulting in motor, cognitive and psychiatric symptoms.

Huntington's is a dominant disease. Elongation of only one allele is sufficient to fry the brain. A second hit doesn't have any addition impact on the disease course. There is