Interaction of huntingtin fragments with brain membranes--clues to early dysfunction in Huntington's disease.
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.
Suopanki
Jaana
J
Max Delbrück Center for Molecular Medicine, Berlin, Germany. j.suopanki@mdc-berlin.de
Götz
Claudia
C
Lutsch
Gudrun
G
Schiller
Jürgen
J
Harjes
Phoebe
P
Herrmann
Andreas
A
Wanker
Erich E
EE
D000367:Age Factors; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001923:Brain Chemistry; D004195:Disease Models, Animal; D005452:Fluoresceins / Q000378:metabolism; D005455:Fluorescent Antibody Technique / Q000379:methods; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015151:Immunoblotting / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011827:Radiation; D018091:Receptors, AMPA / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D013570:Synaptic Membranes / Q000378:metabolism* / Q000473:pathology; D013572:Synaptic Vesicles / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D005452:Fluoresceins; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D010744:Phosphoric Monoester Hydrolases; D018091:Receptors, AMPA; D050486:Serotonin Plasma Membrane Transport Proteins; C493230:SLC6A4 protein, human; C097702:synaptojanin; C007740:fluorexon