期刊
EMBO MOLECULAR MEDICINE
卷 11, 期 1, 页码 -出版社
WILEY
DOI: 10.15252/emmm.201809283
关键词
beta-arrestin; lysosomal degradation; striatum
资金
- Dystonia Medical Research Foundation
- Foundation for Dystonia Research
- Dystonia Medical Research Foundation (DMRF)
- Italian Ministry of Health, Ricerca Finalizzata [RF-2010-2311657]
- Italian Ministry of Health [GR-2011-02351457]
- Alzheimer's Association, United States [AARG-18-566270]
- NATIONAL INSTITUTE OF MENTAL HEALTH [P50MH096890] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS086444] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [P01DA047233] Funding Source: NIH RePORTER
Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early-onset DYT1 dystonia. Nevertheless, the mechanisms that regulate D2 receptor signaling in health and disease remain poorly understood. Here, we identify a reduced D2 receptor binding, paralleled by an abrupt reduction in receptor protein level, in the striatum of juvenile Dyt1 mice. This occurs through increased lysosomal degradation, controlled by competition between beta-arrestin 2 and D2 receptor binding proteins. Accordingly, we found lower levels of striatal RGS9-2 and spinophilin. Further, we show that genetic depletion of RGS9-2 mimics the D2 receptor loss of DYT1 dystonia striatum, whereas RGS9-2 overexpression rescues both receptor levels and electrophysiological responses in Dyt1 striatal neurons. This work uncovers the molecular mechanism underlying D2 receptor downregulation in Dyt1 mice and in turn explains why dopaminergic drugs lack efficacy in DYT1 patients despite significant evidence for striatal D2 receptor dysfunction. Our data also open up novel avenues for disease-modifying therapeutics to this incurable neurological disorder.
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