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News / 10.2.20

Research Roundup: October 2, 2020

Susanna M. Hamilton
Credit : Susanna M. Hamilton
By Broad Communications

Unique interneurons, a cancer dependency explained, the struggle to find prion blockers, and more

Welcome to the October 2, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Not all brains are the same

Postdoctoral fellow Fenna Krienen, institute members Steve McCarroll, Guoping Feng, Gord Fishell, all of the Stanley Center for Psychiatric Research, and colleagues have found several key differences distinguishing human, nonhuman primate, mouse, and ferret brains, all involving a type of neuron called interneurons. Most surprisingly, the team found a new type of interneuron unique to primates, located in the striatum. This region is central to the brain’s motivation and motor systems, is compromised in Huntington’s disease, and is a key site of action for schizophrenia drugs. The findings could help scientists choose lab models that best mimic disease-related features of the human brain. Read more in Nature and a Broad story.

A false sense of stability

In 2019 the Cancer Dependency Map group found that many cancers with microsatellite instability (MSI) rely on the WRN helicase to survive. A multi-center team led at Broad by Edmond Chan and Cancer Program associate member Adam Bass has now identified a mechanism for this vulnerability. Aided by long-read DNA sequencing analyses by Kiran Garimella of Broad's Data Sciences Platform, the team found that specific genomic regions harboring TA dinucleotide repeats expand in MSI-positive cells, over time forming a "genomic scar" that WRN stabilizes. Without WRN, they report in Nature, an MSI cell's chromosomes become increasingly unstable and shatter. 

Therapeutic insights for glioblastoma 

PI3K is an attractive drug target in glioblastoma (GBM), a malignant brain tumor in adults. Cancer Program associate member Jean Zhao and colleagues used genetic and pharmacological approaches to better understand the clinical results of PI3K inhibition in GBM tumors lacking PTEN (which typically blocks PI3K) by studying the actions of two PI3K isoforms, p110α and p110β. Their findings show that p110α promotes GBM proliferation, while p110β plays a major role in tumor invasion. Their findings, presented in Cell Reports, confirm the need to target p110β in future therapeutic efforts.  

Searching for a small molecule

Prion disease is a rapidly progressive neurodegenerative disorder caused by misfolding of the prion protein (PrP). As a potential therapeutic route, Andrew Reidenbach, associated scientist Eric Minikel, and colleagues hunted for small molecules that could bind to the native protein, either to prevent it from misfolding in the first place or to mark it for degradation. Despite deploying a variety of screening methods to discover PrP binders, the researchers observed an exceptionally low hit rate in all cases, suggesting that PrP is a difficult target for this approach. Learn more in Journal of Biological Chemistry and a blog post from Minikel.

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