Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling.
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.
Mesh Terms:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Brain Chemistry, Calcium Channels, Calcium Signaling, Cell Line, Tumor, Dopaminergic Neurons, Down-Regulation, Endoplasmic Reticulum Stress, Humans, Male, Membrane Glycoproteins, Mice, Nerve Tissue Proteins, Neuroblastoma, Parkinsonian Disorders, Proto-Oncogene Proteins c-akt, RNA Interference, RNA, Small Interfering, Stromal Interaction Molecule 1, Substantia Nigra, TOR Serine-Threonine Kinases, TRPC Cation Channels, Unfolded Protein Response
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Brain Chemistry, Calcium Channels, Calcium Signaling, Cell Line, Tumor, Dopaminergic Neurons, Down-Regulation, Endoplasmic Reticulum Stress, Humans, Male, Membrane Glycoproteins, Mice, Nerve Tissue Proteins, Neuroblastoma, Parkinsonian Disorders, Proto-Oncogene Proteins c-akt, RNA Interference, RNA, Small Interfering, Stromal Interaction Molecule 1, Substantia Nigra, TOR Serine-Threonine Kinases, TRPC Cation Channels, Unfolded Protein Response
J Clin Invest
Date: Apr. 01, 2012
PubMed ID: 22446186
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