Protective role of SIRT5 against motor deficit and dopaminergic degeneration in MPTP-induced mice model of Parkinson's disease

Behav Brain Res. 2015 Mar 15;281:215-21. doi: 10.1016/j.bbr.2014.12.035. Epub 2014 Dec 23.

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.

Keywords: Behavior; MPTP; Mitochondria; Parkinson's disease; SIRT5; Sirtuin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / administration & dosage
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Animals
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • MPTP Poisoning / complications
  • MPTP Poisoning / metabolism*
  • MPTP Poisoning / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Motor Activity / drug effects
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology*
  • Neuroprotective Agents / metabolism
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Sirtuins / deficiency
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Superoxide Dismutase / metabolism

Substances

  • Neuroprotective Agents
  • SIRT5 protein, mouse
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Superoxide Dismutase
  • Sirtuins