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The Journal of Neuroscience, October 10, 2007, 27(41):11056-11064; doi:10.1523/JNEUROSCI.1941-07.2007

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Neurobiology of Disease
Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and Protects Caenorhabditis elegans Neurons against Mutant Polyglutamine Toxicity

J. Alex Parker,^1,2 Martina Metzler,³ John Georgiou,⁴ Marilyne Mage,^1,2 John C. Roder,^4,5 Ann M. Rose,⁶ Michael R. Hayden,³ and Christian Néri^1,2

¹Inserm, Unit 857 "Neuronal Cell Biology and Pathology," and ²University of Paris René Descartes, Equipe d'Accueil 4059, Centre Paul Broca, 75014 Paris, France, ³Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4, ⁴Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5, ⁵Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8, and ⁶Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3

Correspondence should be addressed to either Christian Néri or J. Alex Parker, Institut National de la Santé et de la Recherche Médicale, Unit 857 "Neuronal Cell Biology and Pathology," Centre Paul Broca, 75014 Paris, France. Email: neri{at}broca.inserm.fr or Email: parker{at}broca.inserm.fr

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.

Key words: HIP1; synapse; synaptic plasticity; polyglutamine; Huntington's disease; neurodegeneration

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Received April 30, 2007; revised July 30, 2007; accepted Aug. 20, 2007.

Correspondence should be addressed to either Christian Néri or J. Alex Parker, Institut National de la Santé et de la Recherche Médicale, Unit 857 "Neuronal Cell Biology and Pathology," Centre Paul Broca, 75014 Paris, France. Email: neri{at}broca.inserm.fr or Email: parker{at}broca.inserm.fr

This article has been cited by other articles:

				J. L. Marsh, T. Lukacsovich, and L. M. Thompson Animal Models of Polyglutamine Diseases and Therapeutic Approaches J. Biol. Chem., March 20, 2009; 284(12): 7431 - 7435. [Abstract] [Full Text] [PDF]

				T. Kuwahara, A. Koyama, S. Koyama, S. Yoshina, C.-H. Ren, T. Kato, S. Mitani, and T. Iwatsubo A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in {alpha}-synuclein transgenic C. elegans Hum. Mol. Genet., October 1, 2008; 17(19): 2997 - 3009. [Abstract] [Full Text] [PDF]

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