Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling

J Clin Invest. 2012 Apr;122(4):1354-67. doi: 10.1172/JCI61332. Epub 2012 Mar 26.

Abstract

Individuals with Parkinson's disease (PD) experience a progressive decline in motor function as a result of selective loss of dopaminergic (DA) neurons in the substantia nigra. The mechanism(s) underlying the loss of DA neurons is not known. Here, we show that a neurotoxin that causes a disease that mimics PD upon administration to mice, because it induces the selective loss of DA neurons in the substantia nigra, alters Ca²⁺ homeostasis and induces ER stress. In a human neuroblastoma cell line, we found that endogenous store-operated Ca²⁺ entry (SOCE), which is critical for maintaining ER Ca²⁺ levels, is dependent on transient receptor potential channel 1 (TRPC1) activity. Neurotoxin treatment decreased TRPC1 expression, TRPC1 interaction with the SOCE modulator stromal interaction molecule 1 (STIM1), and Ca²⁺ entry into the cells. Overexpression of functional TRPC1 protected against neurotoxin-induced loss of SOCE, the associated decrease in ER Ca²⁺ levels, and the resultant unfolded protein response (UPR). In contrast, silencing of TRPC1 or STIM1 increased the UPR. Furthermore, Ca²⁺ entry via TRPC1 activated the AKT pathway, which has a known role in neuroprotection. Consistent with these in vitro data, Trpc1⁻/⁻ mice had an increased UPR and a reduced number of DA neurons. Brain lysates of patients with PD also showed an increased UPR and decreased TRPC1 levels. Importantly, overexpression of TRPC1 in mice restored AKT/mTOR signaling and increased DA neuron survival following neurotoxin administration. Overall, these results suggest that TRPC1 is involved in regulating Ca²⁺ homeostasis and inhibiting the UPR and thus contributes to neuronal survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology*
  • Animals
  • Brain Chemistry
  • Calcium Channels
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Cell Line, Tumor / metabolism
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / metabolism
  • Down-Regulation / drug effects
  • Endoplasmic Reticulum Stress / drug effects*
  • Humans
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology
  • Mice
  • Nerve Tissue Proteins / physiology
  • Neuroblastoma / pathology
  • Parkinsonian Disorders / metabolism*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / physiology
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Stromal Interaction Molecule 1
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • TOR Serine-Threonine Kinases / physiology*
  • TRPC Cation Channels / biosynthesis*
  • TRPC Cation Channels / genetics
  • TRPC Cation Channels / physiology
  • Unfolded Protein Response / drug effects*

Substances

  • Calcium Channels
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Stim1 protein, mouse
  • Stromal Interaction Molecule 1
  • TRPC Cation Channels
  • transient receptor potential cation channel, subfamily C, member 1
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt