Interaction of huntingtin fragments with brain membranes - clues to early dysfunction in Huntington's disease

Item Type:	Article
Title:	Interaction of huntingtin fragments with brain membranes - clues to early dysfunction in Huntington's disease
Creators Name:	Suopanki, J. and Goetz, C. and Lutsch, G. and Schiller, J. and Harjes, P. and Herrmann, A. and Wanker, E.E.
Abstract:	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.
Keywords:	Fibrillogenesis, Huntingtin, Oligomers, Postsynaptic Membranes
Source:	Journal of Neurochemistry
ISSN:	0022-3042
Publisher:	Blackwell Publishing
Volume:	96
Number:	3
Page Range:	870-884
Date:	February 2006
Official Publication:	https://doi.org/10.1111/j.1471-4159.2005.03620.x
PubMed:	View item in PubMed

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