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.
Highlights
Gene represents the most common cause of both familial and sporadic Amyotrophic lateral sclerosis (ALS),[7,8] responsible for up to 50% of familial ALS and B10% of sporadic ALS, but to date superoxide dismutase 1 enzyme (SOD1) mutations have been the genetic subtype most widely studied and utilized to model ALS
We have previously shown that oculomotor neurons resistant to the disease process in ALS show reduced amino-3-hydroxy5-methyl-4-isoxazole propionic acid (AMPA)-mediated inward calcium currents, and higher GABAmediated chloride currents, compared with spinal MNs that are vulnerable to the disease process.[14]
The aim of the present study was to determine whether PTEN knockdown has an effect on functional AMPA receptor expression and AMPA-mediated cell death in primary cultured and induced pluripotent stem (iPS)-derived MNs
Summary
Gene represents the most common cause of both familial and sporadic ALS,[7,8] responsible for up to 50% of familial ALS and B10% of sporadic ALS, but to date SOD1 mutations have been the genetic subtype most widely studied and utilized to model ALS. An antiexcitotoxic agent, is the only drug proven to slow the disease progression in humans.[10] AMPA receptors have been proposed to play a major role in the selective death of MNs in ALS. These characteristics are related to the way MNs handle Ca2 þ. The aim of the present study is to establish a fibroblast-derived iPS-MN in vitro cell model for manipulation of AMPA receptor expression and function
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