title: Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58201, USA.
authors.forename: Senthil
authors.initials: S
authors.lastname: Selvaraj
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Sun
authors.forename: John A
authors.initials: JA
authors.lastname: Watt
authors.forename: Shouping
authors.initials: S
authors.lastname: Wang
authors.forename: Saobo
authors.initials: S
authors.lastname: Lei
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Brij B
authors.initials: BB
authors.lastname: Singh
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry; D015220:Calcium Channels; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000502:physiology; D009447:Neuroblastoma / Q000473:pathology; D020734:Parkinsonian Disorders / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D000071737:Stromal Interaction Molecule 1; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D050052:TRPC Cation Channels / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D015220:Calcium Channels; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases