Sigma-1 receptor regulates mitophagy in dopaminergic neurons and contributes to dopaminergic protection

Neuropharmacology. 2021 Sep 15:196:108360. doi: 10.1016/j.neuropharm.2020.108360. Epub 2020 Oct 27.

Abstract

Mitochondria are essential for neuronal survival and function, and mitochondrial dysfunction plays a critical role in the pathological development of Parkinson's disease (PD). Mitochondrial quality control is known to contribute to the survival of dopaminergic (DA) neurons, with mitophagy being a key regulator of the quality control system. In this study, we show that mitophagy is impaired in the substantia nigra pars compacta (SNc) of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Treatment with the sigma-1 receptor (Sig 1R) agonist 2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate (PRE-084) reduced loss of DA neurons, restored motor ability and MPTP-induced damage to mitophagy activity in the SNc of PD-like mice. Additionally, knockdown of Sig 1R in SH-SY5Y DA cells inhibited mitophagy and enhanced 1-methyl-4-phenylpyridinium ion (MPP+) neurotoxicity, whereas application of the Sig 1R selective agonist SKF10047 promoted clearance of damaged mitochondria. Moreover, knockdown of Sig 1R in SH-SY5Y cells resulted in decreased levels of p-ULK1 (Unc-51 Like Autophagy Activating Kinase 1) (Ser555), p-TBK1 (TANK Binding Kinase 1) (Ser172), p-ubiquitin (Ub) (Ser65), Parkin recruitment, and stabilization of PTEN-induced putative kinase 1 (PINK1) in mitochondria. The present data provide the first evidence for potential roles of PINK1/Parkin in Sig 1R-modulated mitophagy in DA neurons.

Keywords: Mitophagy; PD; PINK1/Parkin; PRE-084; Sigma-1 receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium / toxicity
  • Animals
  • Autophagy-Related Protein-1 Homolog / drug effects
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Cell Line
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism*
  • Gene Knockdown Techniques
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitophagy / drug effects
  • Mitophagy / genetics*
  • Morpholines / pharmacology
  • Parkinsonian Disorders / genetics
  • Parkinsonian Disorders / metabolism*
  • Parkinsonian Disorders / pathology
  • Pars Compacta / drug effects
  • Pars Compacta / metabolism
  • Pars Compacta / pathology
  • Phenazocine / analogs & derivatives
  • Phenazocine / pharmacology
  • Phosphorylation
  • Protein Kinases / drug effects
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases / drug effects
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Stability / drug effects
  • Protein Transport / drug effects
  • Receptors, sigma / agonists
  • Receptors, sigma / genetics*
  • Receptors, sigma / metabolism
  • Sigma-1 Receptor
  • Signal Transduction
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • Ubiquitin / drug effects
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / drug effects
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Morpholines
  • Receptors, sigma
  • Ubiquitin
  • 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
  • SK&F 10047
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • Tbk1 protein, mouse
  • Autophagy-Related Protein-1 Homolog
  • PTEN-induced putative kinase
  • Protein Serine-Threonine Kinases
  • Ulk1 protein, mouse
  • Phenazocine
  • 1-Methyl-4-phenylpyridinium