Huntingtin-interacting protein 1 influences worm and mouse presynaptic function and protects Caenorhabditis elegans neurons against mutant polyglutamine toxicity.
Huntingtin-interacting protein 1 (HIP1) was identified through its interaction with htt (huntingtin), the Huntington's disease (HD) protein. HIP1 is an endocytic protein that influences transport and function of AMPA and NMDA receptors in the brain. However, little is known about its contribution to neuronal dysfunction in HD. We report that the Caenorhabditis elegans HIP1 homolog hipr-1 modulates presynaptic activity and the abundance of synaptobrevin, a protein involved in synaptic vesicle fusion. Presynaptic function was also altered in hippocampal brain slices of HIP1-/- mice demonstrating delayed recovery from synaptic depression and a reduction in paired-pulse facilitation, a form of presynaptic plasticity. Interestingly, neuronal dysfunction in transgenic nematodes expressing mutant N-terminal huntingtin was specifically enhanced by hipr-1 loss of function. A similar effect was observed with several other mutant proteins that are expressed at the synapse and involved in endocytosis, such as unc-11/AP180, unc-26/synaptojanin, and unc-57/endophilin. Thus, HIP1 is involved in presynaptic nerve terminal activity and modulation of mutant polyglutamine-induced neuronal dysfunction. Moreover, synaptic proteins involved in endocytosis may protect neurons against amino acid homopolymer expansion.
Parker
J Alex
JA
Inserm, Unit 857 Neuronal Cell Biology and Pathology, Centre Paul Broca, 75014 Paris, France. parker@broca.inserm.fr
Metzler
Martina
M
Georgiou
John
J
Mage
Marilyne
M
Roder
John C
JC
Rose
Ann M
AM
Hayden
Michael R
MR
Néri
Christian
C
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000633:toxicity*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000235:genetics / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; C073368:HIP1 protein, human; D010455:Peptides; C097188:polyglutamine