title: Dysregulation of parkin in the substantia nigra of db/db and high-fat diet mice.
abstract: 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.
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
authors.forename: R
authors.initials: R
authors.lastname: Khang
authors.affiliation: Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea; Mass Spectrometry, Research Core Facility, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
authors.forename: C
authors.initials: C
authors.lastname: Park
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea; Mass Spectrometry, Research Core Facility, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea. Electronic address: jshin24@skku.edu.
authors.forename: J-H
authors.initials: JH
authors.lastname: Shin
mesh_terms: D000821:Animal Feed; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D059305:Diet, High-Fat; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins; C557561:ZNF746 protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine
keywords: PARIS; Parkinson’s disease; metformin; parkin; type 2 diabetes