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

Senthil Selvaraj, Yuyang Sun, John A. Watt, Shouping Wang, Saobo Lei, Lutz Birnbaumer, Brij B. Singh

Research output: Contribution to journalArticle

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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 Ca 2+ homeostasis and induces ER stress. In a human neuroblastoma cell line, we found that endogenous store-operated Ca 2+ entry (SOCE), which is critical for maintaining ER Ca 2+ 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 Ca 2+ entry into the cells. Overexpression of functional TRPC1 protected against neurotoxin-induced loss of SOCE, the associated decrease in ER Ca 2+levels, and the resultant unfolded protein response (UPR). In contrast, silencing of TRPC1 or STIM1 increased the UPR. Furthermore, Ca 2+ 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 Ca 2+homeostasis and inhibiting the UPR and thus contributes to neuronal survival.

Original languageEnglish
Pages (from-to)1354-1367
Number of pages14
JournalJournal of Clinical Investigation
Volume122
Issue number4
DOIs
Publication statusPublished - 2 Apr 2012
Externally publishedYes

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Transient Receptor Potential Channels
Dopaminergic Neurons
Neurotoxins
Down-Regulation
Unfolded Protein Response
Parkinson Disease
Substantia Nigra
Homeostasis
Neuroblastoma
Cell Line

ASJC Scopus subject areas

  • Medicine(all)

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Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling. / Selvaraj, Senthil; Sun, Yuyang; Watt, John A.; Wang, Shouping; Lei, Saobo; Birnbaumer, Lutz; Singh, Brij B.

In: Journal of Clinical Investigation, Vol. 122, No. 4, 02.04.2012, p. 1354-1367.

Research output: Contribution to journalArticle

Selvaraj, Senthil ; Sun, Yuyang ; Watt, John A. ; Wang, Shouping ; Lei, Saobo ; Birnbaumer, Lutz ; Singh, Brij B. / Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 4. pp. 1354-1367.
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