Disruption of the endocytic protein HIP1 results in neurological deficits and decreased AMPA receptor trafficking |
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| Authors: | Metzler Martina Li Bo Gan Lu Georgiou John Gutekunst Claire-Anne Wang Yushan Torre Enrique Devon Rebecca S Oh Rosemary Legendre-Guillemin Valerie Rich Mark Alvarez Christine Gertsenstein Marina McPherson Peter S Nagy Andras Wang Yu Tian Roder John C Raymond Lynn A Hayden Michael R |
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| Affiliation: | Centre for Molecular Medicine and Therapeutics, Childrens and Womens Hospital, Department of Medical Genetics, University of British Columbia, Vancouver, BC, V5Z 4H4. |
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| Abstract: | Huntingtin interacting protein 1 (HIP1) is a recently identified component of clathrin-coated vesicles that plays a role in clathrin-mediated endocytosis. To explore the normal function of HIP1 in vivo, we created mice with targeted mutation in the HIP1 gene (HIP1(-/-)). HIP1(-/-) mice develop a neurological phenotype by 3 months of age manifest with a failure to thrive, tremor and a gait ataxia secondary to a rigid thoracolumbar kyphosis accompanied by decreased assembly of endocytic protein complexes on liposomal membranes. In primary hippocampal neurons, HIP1 colocalizes with GluR1-containing AMPA receptors and becomes concentrated in cell bodies following AMPA stimulation. Moreover, a profound dose-dependent defect in clathrin-mediated internalization of GluR1-containing AMPA receptors was observed in neurons from HIP1(-/-) mice. Together, these data provide strong evidence that HIP1 regulates AMPA receptor trafficking in the central nervous system through its function in clathrin-mediated endocytosis. |
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