期刊
JCI INSIGHT
卷 2, 期 9, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.88995
关键词
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资金
- Cure Huntington's Disease Initiative (CHDI) Foundation
- National Institute of Health [NS030687, NS064114, HL96571, HL098351, DA08259]
- Hereditary Disease Foundation
- Hereditary Neurological Disease Centre-Wichita
- Intramural Research Program of National Institute of Health
- National Cancer Institute
- Center for Cancer Research
- NIH Intramural Research Program
- Center for Cancer Research, National Cancer Institute
Motor dysfunction is a prominent and disabling feature of Huntington's disease (HD), but the molecular mechanisms that dictate its onset and progression are unknown. The N-methyl-Daspartate receptor 2A (NR2A) subunit regulates motor skill development and synaptic plasticity in medium spiny neurons (MSNs) of the striatum, cells that are most severely impacted by HD. Here, we document reduced NR2A receptor subunits on the dendritic membranes and at the synapses of MSNs in zQ175 mice that model HD. We identify that SorCS2, a vacuolar protein sorting 10 protein-domain (VPS10P-domain) receptor, interacts with VPS35, a core component of retromer, thereby regulating surface trafficking of NR2A in MSNs. In the zQ175 striatum, SorCS2 is markedly decreased in an age-and allele-dependent manner. Notably, SorCS2 selectively interacts with mutant huntingtin (mtHTT), but not WT huntingtin (wtHTT), and is mislocalized to perinuclear clusters in striatal neurons of human HD patients and zQ175 mice. Genetic deficiency of SorCS2 accelerates the onset and exacerbates the motor coordination deficit of zQ175 mice. Together, our results identify SorCS2 as an interacting protein of mtHTT and demonstrate that impaired SorCS2mediated NR2A subunit trafficking to dendritic surface of MSNs is, to our knowledge, a novel mechanism contributing to motor coordination deficits of HD.
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