Mutant huntingtin causes defective actin remodeling during stress: defining a new role for transglutaminase 2 in neurodegenerative disease

Hum Mol Genet. 2011 May 15;20(10):1937-51. doi: 10.1093/hmg/ddr075. Epub 2011 Feb 25.


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-Förster 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Depolymerizing Factors / metabolism
  • Actins / metabolism*
  • Animals
  • Cell Line
  • Cytoskeletal Proteins / metabolism
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Gene Expression / genetics
  • Heat-Shock Response / genetics*
  • Hot Temperature
  • Humans
  • Huntingtin Protein
  • Huntington Disease / enzymology*
  • Huntington Disease / genetics*
  • Intracellular Space / metabolism
  • Lymphocytes / metabolism
  • Mice
  • Models, Biological
  • Mutation / genetics*
  • NIH 3T3 Cells
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Protein Transport
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Transglutaminases / genetics
  • Transglutaminases / metabolism*


  • Actin Depolymerizing Factors
  • Actins
  • Cytoskeletal Proteins
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • transglutaminase 2
  • Transglutaminases
  • GTP-Binding Proteins