Abstract
The article by McConoughey et al in the current issue of EMBO Molecular Medicine examines the contribution of transglutaminase 2 (TG2) to Huntington's disease (HD) pathogenesis. The authors find that TG2 inhibition can ameliorate HD neurodegeneration, and thereby elevate the status of transglutaminases (TGs) to a major therapeutic target—not because of their well-known activity in mutant protein aggregation, but instead based upon their ability to epigenetically modulate transcription and energy production. While the reintroduction of TG inhibition as a therapy for HD may evoke feelings of déjà vu, the outcome this time around could go in a dramatically different direction.
Highlights
The rapid ascension of TGs as mediators of polyQ toxicity soon met with serious skepticism
The involvement of TGs in the polyQ disorders was corroborated by evidence from patient samples, where total TG activity was elevated in brain extracts from Huntington’s disease (HD) patients (Karpuj et al, 1999), and an isodipeptide, a biomarker of TG activity, was elevated over threefold in HD cerebrospinal fluid compared to control (Jeitner et al, 2001)
Initial hints that TGs are involved in both bioenergetics and transcriptional dysfunction due to expanded polyQ proteins came from two sets of studies from the same group
Summary
The rapid ascension of TGs as mediators of polyQ toxicity soon met with serious skepticism. (2) Department of Cellular & Molecular Medicine, University of California, San Diego – La Jolla, CA, USA.
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