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Interaction of huntingtin fragments with brain membranes – clues to early dysfunction in Huntington's disease
Author(s) -
Suopanki Jaana,
Götz Claudia,
Lutsch Gudrun,
Schiller Jürgen,
Harjes Phoebe,
Herrmann Andreas,
Wanker Erich E.
Publication year - 2006
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.1471-4159.2005.03620.x
Subject(s) - huntingtin , huntingtin protein , microbiology and biotechnology , ampa receptor , biology , huntington's disease , neurodegeneration , polyglutamine tract , exon , chemistry , mutant , biochemistry , nmda receptor , receptor , medicine , gene , disease
Huntingtin is a large, multi‐domain protein of unknown function in the brain. An abnormally elongated polyglutamine stretch in its N‐terminus causes Huntington's disease (HD), a progressive neurodegenerative disorder. Huntingtin has been proposed to play a functional role in membrane trafficking via proteins involved in endo‐ and exocytosis. Here, we supply evidence for a direct association between huntingtin and membranes. In the brains of R6/2 mice with HD pathology, a 64 kDa N‐terminal huntingtin fragment accumulated in postsynaptic membranes during the pre‐symptomatic period of 4–8 weeks of age. In addition, an oligomeric fragment of approximately 200 kDa was detected at 8 weeks of age. Simultaneous progressive changes in distribution of amphiphysin, synaptojanin, and subunits of NMDA‐ and AMPA‐receptors provide a strong indication of dysfunctional synaptic trafficking. Composition of the major phospholipids in the synaptic membranes was unaffected. In vitro , large unilamellar vesicles of brain lipids readily associated with soluble N‐terminal huntingtin exon 1 fragments and stimulated fibrillogenesis of mutant huntingtin aggregates. Moreover, interaction of both mutant and wild‐type huntingtin exon 1 fragments with brain lipids caused bilayer perturbation, mediated through a proline‐rich region adjacent to the polyglutamines. This suggests that lipid interactions in vivo could influence misfolding of huntingtin and may play an early role in HD pathogenesis.