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Polyglutamine expansion in huntingtin alters its interaction with phospholipids
Author(s) -
Kegel Kimberly B.,
Sapp Ellen,
Alexander Jonathan,
Valencia Antonio,
Reeves Patrick,
Li Xueyi,
Masso Nicholas,
Sobin Lindsay,
Aronin Neil,
DiFiglia Marian
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06255.x
Subject(s) - huntingtin , chemistry , neuroscience , biology , microbiology and biotechnology , biochemistry , gene , mutant
Huntingtin has an expanded polyglutamine tract in patients with Huntington’s disease. Huntingtin localizes to intracellular and plasma membranes but the function of huntingtin at membranes is unknown. Previously we reported that exogenously expressed huntingtin bound pure phospholipids using protein‐lipid overlays. Here we show that endogenous huntingtin from normal ( Hdh 7Q/7Q ) mouse brain and mutant huntingtin from Huntington’s disease ( Hdh 140Q/140Q ) mouse brain bound to large unilamellar vesicles containing phosphoinositol (PI) PI 3,4‐bisphosphate, PI 3,5‐bisphosphate, and PI 3,4,5‐triphosphate [PI(3,4,5)P3]. Huntingtin interactions with multivalent phospholipids were similar to those of dynamin. Mutant huntingtin associated more with phosphatidylethanolamine and PI(3,4,5)P3 than did wild‐type huntingtin, and associated with other phospholipids not recognized by wild‐type huntingtin. Wild‐type and mutant huntingtin also bound to large unilamellar vesicles containing cardiolipin, a phospholipid specific to mitochondrial membranes. Maximal huntingtin‐phospholipid association required inclusion of huntingtin amino acids 171–287. Endogenous huntingtin recruited to the plasma membrane in cells that incorporated exogenous PI 3,4‐bisphosphate and PI(3,4,5)P3 or were stimulated by platelet‐derived growth factor or insulin growth factor 1, which both activate PI 3‐kinase. These data suggest that huntingtin interacts with membranes through specific phospholipid associations and that mutant huntingtin may disrupt membrane trafficking and signaling at membranes.