ROCK1 induces dopaminergic nerve cell apoptosis via the activation of Drp1-mediated aberrant mitochondrial fission in Parkinson's disease

Exp Mol Med. 2019 Oct 2;51(10):1-13. doi: 10.1038/s12276-019-0318-z.

Abstract

Dopamine deficiency is mainly caused by apoptosis of dopaminergic nerve cells in the substantia nigra of the midbrain and the striatum and is an important pathologic basis of Parkinson's disease (PD). Recent research has shown that dynamin-related protein 1 (Drp1)-mediated aberrant mitochondrial fission plays a crucial role in dopaminergic nerve cell apoptosis. However, the upstream regulatory mechanism remains unclear. Our study showed that Drp1 knockdown inhibited aberrant mitochondrial fission and apoptosis. Importantly, we found that ROCK1 was activated in an MPP+-induced PD cell model and that ROCK1 knockdown and the specific ROCK1 activation inhibitor Y-27632 blocked Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic nerve cells by suppressing Drp1 dephosphorylation/activation. Our in vivo study confirmed that Y-27632 significantly improved symptoms in a PD mouse model by inhibiting Drp1-mediated aberrant mitochondrial fission and apoptosis. Collectively, our findings suggest an important molecular mechanism of PD pathogenesis involving ROCK1-regulated dopaminergic nerve cell apoptosis via the activation of Drp1-induced aberrant mitochondrial fission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium / administration & dosage
  • Amides / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Dopamine / deficiency*
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • Dynamins / antagonists & inhibitors
  • Dynamins / genetics*
  • Dynamins / metabolism
  • Gene Expression Regulation
  • Humans
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Dynamics / drug effects
  • Oxidative Stress
  • PC12 Cells
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / drug therapy
  • Parkinson Disease, Secondary / genetics*
  • Parkinson Disease, Secondary / pathology
  • Pyridines / pharmacology
  • Rats
  • Signal Transduction
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • rho-Associated Kinases / deficiency
  • rho-Associated Kinases / genetics*

Substances

  • Amides
  • Pyridines
  • Y 27632
  • Rock1 protein, mouse
  • rho-Associated Kinases
  • Dnm1l protein, mouse
  • Dynamins
  • 1-Methyl-4-phenylpyridinium
  • Dopamine