| First Author | Selvaraj S | Year | 2012 |
| Journal | J Clin Invest | Volume | 122 |
| Issue | 4 | Pages | 1354-67 |
| PubMed ID | 22446186 | Mgi Jnum | J:184546 |
| Mgi Id | MGI:5424302 | Doi | 10.1172/JCI61332 |
| Citation | Selvaraj S, et al. (2012) Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling. J Clin Invest 122(4):1354-67 |
| abstractText | 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. |
