title: Protective role of SIRT5 against motor deficit and dopaminergic degeneration in MPTP-induced mice model of Parkinson's disease.
abstract: Parkinson's disease (PD) is characterized by progressive loss of nigrostriatal dopaminergic neurons that results in motor deficits including resting tremor, rigidity, bradykinesia, and postural instability. Despite decades of intensive study, the underlying molecular mechanisms are not fully understood. Multiple lines of evidence indicate that mitochondrial dysfunction and oxidative stress contribute to neuronal death, which is the key feature of neurodegeneration. Mitochondria are pivotal organelles that host essential functions in neuronal viability including energy production, oxidative phosphorylation, calcium buffering, redox homeostasis and apoptosis. SIRT5, which localizes in the mitochondrial matrix, is nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylase. The physiological and pathophysiological functions of SIRT5 in vivo remain elusive although it is known to be an important energy sensor. Here, we investigated the role of SIRT5 in the pathogenesis of PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We present evidence that SIRT5 deficiency, by itself, does not affect motor and non-motor functions; however, lack of SIRT5 exacerbates MPTP-induced motor deficits. Consistently, MPTP-exposed SIRT5 knockout mice exhibited more severe nigrostriatal dopaminergic degeneration than that observed in wild-type controls. Furthermore, deletion of SIRT5 leads to a larger decrease, relative to control, in the expression level of manganese superoxide dismutase (SOD2), a mitochondria-specific antioxidant enzyme, after MPTP induction. These findings indicate that SIRT5 ameliorates MPTP-induced nigrostriatal dopaminergic degeneration via preserving mitochondrial antioxidant capacity.
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Carina
authors.initials: C
authors.lastname: Peritore
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ginsberg
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Shih
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Arun
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA. Electronic address: Gizem.Donmez@tufts.edu.
authors.forename: Gizem
authors.initials: G
authors.lastname: Donmez
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D020267:MPTP Poisoning / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; C542554:SIRT5 protein, mouse; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D013482:Superoxide Dismutase; D037761:Sirtuins
keywords: Behavior; MPTP; Mitochondria; Parkinson's disease; SIRT5; Sirtuin