Developing HDAC4-Selective Protein Degraders To Investigate the Role of HDAC4 in Huntington’s Disease Pathology
Year: 2022
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide Huntington’s disease (HD) is a lethal autosomal dominant neurodegenerative disorder resulting from a CAG repeat expansion in the huntingtin ( HTT ) gene. The product of translation of this gene is a highly aggregation-prone protein containing a polyglutamine tract >35 repeats (mHTT) that has been shown to colocalize with histone deacetylase 4 (HDAC4) in cytoplasmic inclusions in HD mouse models. Genetic reduction of HDAC4 in an HD mouse model resulted in delayed aggregation of mHTT, along with amelioration of neurological phenotypes and extended lifespan. To further investigate the role of HDAC4 in cellular models of HD, we have developed bifunctional degraders of the protein and report the first potent and selective degraders of HDAC4 that show an effect in multiple cell lines, including HD mouse model-derived cortical neurons. These degraders act via the ubiquitin-proteasomal pathway and selectively degrade HDAC4 over other class IIa HDAC isoforms (HDAC5, HDAC7, and HDAC9).
Source: Journal of Medicinal Chemistry
Authors: Natsuko Macabuag, William Esmieu, Perla Breccia, Rebecca Jarvis, Wesley Blackaby, Ovadia Lazari, Liudvikas Urbonas, Maria Eznarriaga, Rachel Williams, Annelieke Strijbosch, Rhea Van de Bospoort, Kim Matthews, Cole Clissold, Tammy Ladduwahetty, Huw Vater, Patrick Heaphy, Douglas G. Stafford, Hong-Jun Wang, John E. Mangette, George McAllister, Vahri Beaumont, Thomas F. Vogt, Hilary A. Wilkinson, Elizabeth M. Doherty, Celia Dominguez
Institutions: Charles River Laboratories (Netherlands), CHDI Foundation
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
OpenAlex ID: W4295367113