Dysregulation of parkin in the substantia nigra of db/db and high-fat diet mice.

Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the substantia nigra (SN). Epidemiological evidence has suggested a link between type 2 diabetes and PD, although the mechanisms remain largely unknown. We applied LC-MS/MS-based pattern analysis to investigate altered proteomes in the SN of db/db mice (db-SN) and high-fat diet mice (HFD-SN), revealing that the level of mitochondrial proteins has changed in the SN of diabetic mice compared to that of control mice. Since mitochondrial proteins were robustly altered in db-SN and HFD-SN, we performed immunoblot analysis to monitor the level of parkin, PINK1 (phosphatase and tensin homolog-induced putative kinase 1) and DJ-1 that were directly involved in mitochondrial dynamics. As a result, PINK1 and DJ-1 level was unchanged, whereas a significant loss of parkin was found in db-SN and HFD-SN, leading to the accumulation of parkin-interacting substrate (PARIS) and the reduction of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Interestingly, these alterations were reversed by the administration of metformin, one of most frequently prescribed anti-hyperglycemic agents. The slight loss of dopaminergic neurons was found in chronic HFD-SN that was restored by metformin. Taken together, our data suggest that the dysregulation of Parkin-PARIS-PGC-1α pathway by metabolic malregulation may contribute to the pathogenesis of PD and metformin might exert a neuroprotective effect on PD via the restoration of parkin.