Journal
HUMAN MOLECULAR GENETICS
Volume 20, Issue 10, Pages 1937-1951Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr075
Keywords
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Funding
- Canadian Institutes of Health Research [MOP-165174]
- Krembil Foundation
- CHDI Inc.
- MRC
- Wellcome Trust
- CHDI
- Brain Research Trust
- UK Department of Health's NIHR Biomedical Research Centers
- NIH [NS40371]
- MRC [G0700877] Funding Source: UKRI
- Medical Research Council [G0700877] Funding Source: researchfish
- National Institute for Health Research [CL-2009-18-005] Funding Source: researchfish
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Huntington's disease (HD) is caused by an expanded CAG tract in the Interesting transcript 15 (IT15) gene encoding the 350 kDa huntingtin protein. Cellular stresses can trigger the release of huntingtin from the endoplasmic reticulum, allowing huntingtin nuclear entry. Here, we show that endogenous, full-length huntingtin localizes to nuclear cofilin-actin rods during stress and is required for the proper stress response involving actin remodeling. Mutant huntingtin induces a dominant, persistent nuclear rod phenotype similar to that described in Alzheimer's disease for cytoplasmic cofilin-actin rods. Using live cell temporal studies, we show that this stress response is similarly impaired when mutant huntingtin is present, or when normal huntingtin levels are reduced. In clinical lymphocyte samples from HD patients, we have quantitatively detected cross-linked complexes of actin and cofilin with complex formation varying in correlation with disease progression. By live cell fluorescence lifetime imaging measurement-Forster resonant energy transfer studies and western blot assays, we quantitatively observed that stress-activated tissue transglutaminase 2 (TG2) is responsible for the actin-cofilin covalent cross-linking observed in HD. These data support a direct role for huntingtin in nuclear actin re-organization, and describe a new pathogenic mechanism for aberrant TG2 enzymatic hyperactivity in neurodegenerative diseases.
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