Interaction of huntingtin fragments with brain membranes – clues to early dysfunction in Huntington's 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.