title: PTEN regulates AMPA receptor-mediated cell viability in iPS-derived motor neurons.
abstract: Excitatory transmission in the brain is commonly mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In amyotrophic lateral sclerosis (ALS), AMPA receptors allow cytotoxic levels of calcium into neurons, contributing to motor neuron injury. We have previously shown that oculomotor neurons resistant to the disease process in ALS show reduced AMPA-mediated inward calcium currents compared with vulnerable spinal motor neurons. We have also shown that PTEN (phosphatase and tensin homolog deleted on chromosome 10) knockdown via siRNA promotes motor neuron survival in models of spinal muscular atrophy (SMA) and ALS. It has been reported that inhibition of PTEN attenuates the death of hippocampal neurons post injury by decreasing the effective translocation of the GluR2 subunit into the membrane. In addition, leptin can regulate AMPA receptor trafficking via PTEN inhibition. Thus, we speculate that manipulation of AMPA receptors by PTEN may represent a potential therapeutic strategy for neuroprotective intervention in ALS and other neurodegenerative disorders. To this end, the first step is to establish a fibroblast-iPS-motor neuron in vitro cell model to study AMPA receptor manipulation. Here we report that iPS-derived motor neurons from human fibroblasts express AMPA receptors. PTEN depletion decreases AMPA receptor expression and AMPA-mediated whole-cell currents, resulting in inhibition of AMPA-induced neuronal death in primary cultured and iPS-derived motor neurons. Taken together, our results imply that PTEN depletion may protect motor neurons by inhibition of excitatory transmission that represents a therapeutic strategy of potential benefit for the amelioration of excitotoxicity in ALS and other neurodegenerative disorders.
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: D-J
authors.initials: DJ
authors.lastname: Yang
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: X-L
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: A
authors.initials: A
authors.lastname: Ismail
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Ashman
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: C F
authors.initials: CF
authors.lastname: Valori
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: S
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: A
authors.initials: A
authors.lastname: Higginbottom
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: P G
authors.initials: PG
authors.lastname: Ince
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: M
authors.initials: M
authors.lastname: Azzouz
authors.affiliation: East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: 1] East Hospital, Tongji University School of Medicine, Shanghai, China [2] Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: K
authors.initials: K
authors.lastname: Ning
mesh_terms: D000328:Adult; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000637:transplantation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000637:transplantation; D008564:Membrane Potentials; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000637:transplantation; D058953:Neural Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000637:transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D034622:RNA Interference; D018091:Receptors, AMPA / Q000378:metabolism*; D015398:Signal Transduction; D009435:Synaptic Transmission; D013724:Teratoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
chemical_list: D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse