Distinct Roles for μ-Calpain and m-Calpain in Synaptic NMDAR-Mediated Neuroprotection and Extrasynaptic NMDAR-Mediated Neurodegeneration DOI Creative Commons
Yubin Wang, Víctor Briz, Athar H. Chishti

et al.

Journal of Neuroscience, Journal Year: 2013, Volume and Issue: 33(48), P. 18880 - 18892

Published: Nov. 27, 2013

Prolonged calpain activation is widely recognized as a key component of neurodegeneration in variety pathological conditions. Numerous reports have also indicated that synaptic NMDA receptors (NMDARs) provides neuroprotection against insults. Here, we report the paradoxical finding such involves activation. NMDAR cultured rat cortical neurons was neuroprotective starvation and oxidative stress-induced damage. It resulted degradation two splice variants PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1), PHLPP1α PHLPP1β, which inhibit Akt ERK1/2 pathways. Synaptic NMDAR-induced PHLPP1 were blocked by inhibition. Lentiviral knockdown mimicked effects occluded inhibition on neuroprotection. In contrast to activation, extrasynaptic had no effect pathways, but calpain-mediated striatal-enriched protein tyrosine phosphatase (STEP) neuronal death. Using μ-calpain- m-calpain-selective inhibitors μ-calpain m-calpain siRNAs, found μ-calpain-dependent cleavage involved NMDAR-mediated neuroprotection, while m-calpain-mediated STEP associated with neurotoxicity. Furthermore, reduced knockout exacerbated NMDA-induced neurotoxicity acute mouse hippocampal slices. Thus, NMDAR-coupled neuroprotective, neurodegenerative. These results help reconcile number contradictory literature critical implications for understanding potential treatment neurodegenerative diseases.

Language: Английский

Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2 DOI Creative Commons
Takuto Hideyama,

Takenari Yamashita,

Takeshi Suzuki

et al.

Journal of Neuroscience, Journal Year: 2010, Volume and Issue: 30(36), P. 11917 - 11925

Published: Sept. 8, 2010

GluR2 is a subunit of the AMPA receptor, and adenosine for Q/R site its pre-mRNA converted to inosine (A-to-I conversion) by enzyme called deaminase acting on RNA 2 (ADAR2). Failure A-to-I conversion at this affects multiple receptor properties, including Ca 2+ permeability receptor-coupled ion channel, thereby inducing fatal epilepsy in mice (Brusa et al., 1995; Feldmeyer 1999). In addition, inefficient editing disease-specific molecular dysfunction found motor neurons sporadic amyotrophic lateral sclerosis (ALS) patients (Kawahara 2004). Here, we generated genetically modified (designated as AR2) which ADAR2 gene was conditionally targeted using Cre/loxP system. These AR2 showed decline function commensurate with slow death ADAR2-deficient spinal cord cranial nerve nuclei. Notably, nuclei oculomotor nerves, often escape degeneration ALS, were not decreased number despite significant decrease editing. All cellular phenotypic changes prevented when carried endogenous alleles engineered express edited without activity (Higuchi 2000). Thus, loss causes receptor-mediated neurons.

Language: Английский

Citations

150
N-Methyl-d-aspartate Receptor- and Calpain-mediated Proteolytic Cleavage of K+-Cl− Cotransporter-2 Impairs Spinal Chloride Homeostasis in Neuropathic Pain DOI Creative Commons
Hongyi Zhou,

Shao-Rui Chen,

Hee‐Sun Byun

et al.

Journal of Biological Chemistry, Journal Year: 2012, Volume and Issue: 287(40), P. 33853 - 33864

Published: Aug. 2, 2012

Language: Английский

Citations

139
Mechanism of Pyrethroid Pesticide–Induced Apoptosis: Role of Calpain and the ER Stress Pathway DOI Open Access
Muhammad M. Hossain, Jason R. Richardson

Toxicological Sciences, Journal Year: 2011, Volume and Issue: 122(2), P. 512 - 525

Published: May 9, 2011

Exposure to the pyrethroid pesticide deltamethrin has been demonstrated cause apoptosis both in vitro and vivo. However, molecular pathways leading deltamethrin-induced have not established. To identify these pathways, SK-N-AS neuroblastoma cells were exposed (100nM–5μM) for 24–48 h. Deltamethrin produced a time- dose-dependent increase (21–300%) DNA fragmentation, an indicator of apoptosis. Data demonstrate that initiation fragmentation resulted from interaction with Na+ channels consequent calcium influx, as tetrodotoxin intracellular Ca2+ chelator BAPTA-AM completely prevented was accompanied by increased caspase-9 -3 activities abolished specific inhibitors. did cytosolic cytochrome c levels, indicating mitochondrial pathway likely involved. Additional studies exposure activated caspase-12 activity pharmacological inhibition siRNA knockdown calpain thus role endoplasmic reticulum (ER) stress pathway. This confirmed observation eIF2α fragmentation. Together, data causes through its channels, overload activation ER Because subsequent unfolded protein response observed number neurodegenerative diseases, provide mechanistic information which high-level pyrethroids may contribute neurodegeneration.

Language: Английский

Citations

139
Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach DOI Creative Commons
Andrew F. Teich, Russell E. Nicholls, Daniela Puzzo

et al.

Neurotherapeutics, Journal Year: 2015, Volume and Issue: 12(1), P. 29 - 41

Published: Jan. 1, 2015

Language: Английский

Citations

136
Distinct Roles for μ-Calpain and m-Calpain in Synaptic NMDAR-Mediated Neuroprotection and Extrasynaptic NMDAR-Mediated Neurodegeneration DOI Creative Commons
Yubin Wang, Víctor Briz, Athar H. Chishti

et al.

Journal of Neuroscience, Journal Year: 2013, Volume and Issue: 33(48), P. 18880 - 18892

Published: Nov. 27, 2013

Prolonged calpain activation is widely recognized as a key component of neurodegeneration in variety pathological conditions. Numerous reports have also indicated that synaptic NMDA receptors (NMDARs) provides neuroprotection against insults. Here, we report the paradoxical finding such involves activation. NMDAR cultured rat cortical neurons was neuroprotective starvation and oxidative stress-induced damage. It resulted degradation two splice variants PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1), PHLPP1α PHLPP1β, which inhibit Akt ERK1/2 pathways. Synaptic NMDAR-induced PHLPP1 were blocked by inhibition. Lentiviral knockdown mimicked effects occluded inhibition on neuroprotection. In contrast to activation, extrasynaptic had no effect pathways, but calpain-mediated striatal-enriched protein tyrosine phosphatase (STEP) neuronal death. Using μ-calpain- m-calpain-selective inhibitors μ-calpain m-calpain siRNAs, found μ-calpain-dependent cleavage involved NMDAR-mediated neuroprotection, while m-calpain-mediated STEP associated with neurotoxicity. Furthermore, reduced knockout exacerbated NMDA-induced neurotoxicity acute mouse hippocampal slices. Thus, NMDAR-coupled neuroprotective, neurodegenerative. These results help reconcile number contradictory literature critical implications for understanding potential treatment neurodegenerative diseases.

Language: Английский

Citations

135