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Mutant Huntington Protein Forms Channels in Lipid Membranes
Author(s) -
Azimova Rushania K,
Schweitzer Erik S,
Fischer Torsten,
Kagan Bruce L
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a330-b
Subject(s) - huntingtin , ion channel , mutant , chemistry , microbiology and biotechnology , lipid bilayer , exon , huntingtin protein , biochemistry , membrane , biology , biophysics , gene , receptor
Huntington’s Disease (HD) is a hereditary neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. HD is caused by polyglutamine repeat expansion in the first exon of the huntingtin (Htt) protein. Extended tracts of polyglutamine (PG) have been implicated in the pathogenicity of the mutant protein Htt and have been shown to form ion channels in planar lipid bilayer membranes (BLM). We report here that a Htt mutant protein comprising the first exon of Htt with a 46 residue PG repeat can induce large long‐lived ion channels in BLM. Channel formation is enhanced at acidic pH. A comparable mutant containing a 25 residue PG repeat does not form channels. These lines of evidence suggest that Htt and other PG mutant proteins may damage cells via a channel forming mechanism, that could cause damage to the plasma membrane by running down ionic gradients discharging membrane potential, allowing influx of toxic ions such as Ca(2+). Htt may damage intracellular membranes such as the lysomal or the mitochondrial membrane via leakage of toxic enzymes or triggering of apoptosis. We propose that channel formation by Htt may be a mechanism of cellular toxicity as well established for microbial toxins and the existence of at least six other “amyloid” channels relevant to diseases such as Alzheimer’s and Creutzfeld‐Jakob, suggests that this may be a widespread pathogenic mechanism. Supported by Alzheimer Association 441587‐DS‐58580