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• W2011103525 abstract "It is unclear why motor neurons selectively degenerate in amyotrophic lateral sclerosis (ALS). Saxena et al., 2013Saxena S. Roselli F. Singh K. Leptien K. Julien J.-P. Gros-Louis F. Caroni P. Neuron. 2013; 80 (this issue): 80-96Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar demonstrate that excitation of motor neurons can prevent their demise in a mouse model of inherited ALS by a mechanism involving the mTOR pathway. It is unclear why motor neurons selectively degenerate in amyotrophic lateral sclerosis (ALS). Saxena et al., 2013Saxena S. Roselli F. Singh K. Leptien K. Julien J.-P. Gros-Louis F. Caroni P. Neuron. 2013; 80 (this issue): 80-96Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar demonstrate that excitation of motor neurons can prevent their demise in a mouse model of inherited ALS by a mechanism involving the mTOR pathway. People with amyotrophic lateral sclerosis (ALS) suffer progressive weakness, paralysis, and death as a result of the dysfunction and degeneration of lower and upper motor neurons (MNs). While in most cases the causes of ALS are unknown, for some an inherited genetic defect is responsible. Mutations that cause familial ALS (FALS) include those in genes encoding superoxide dismutase 1 (SOD1), TDP-43, Ubiquilin-2 and FUS, and a hexanucleotide repeat in a noncoding region on chromosome 9 (C9orf72) (Turner et al., 2013Turner M.R. Hardiman O. Benatar M. Brooks B.R. Chio A. de Carvalho M. Ince P.G. Lin C. Miller R.G. Mitsumoto H. et al.Lancet Neurol. 2013; 12: 310-322Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). Transgenic mice expressing mutant human SOD1 (mutSOD1) are a widely used ALS model as they develop progressive MN degeneration and paralysis similar to ALS patients. MNs in mutSOD1 mice accumulate SOD1 protein aggregates and exhibit mitochondrial dysfunction. Studies of ALS patients and animal models suggest that MNs may suffer excitotoxicity, a neurodegenerative process involving excessive activation of glutamate receptors and cellular Ca2+ overload. Impaired uptake of glutamate by astrocytes may contribute to excitotoxicity in ALS, and currently the only drug that has demonstrated a disease-modifying effect in ALS patients is believed to act by reducing excitation of MNs (Rothstein, 2009Rothstein J.D. Ann. Neurol. 2009; 65: S3-S9Crossref PubMed Google Scholar). Surprisingly, Saxena et al., 2013Saxena S. Roselli F. Singh K. Leptien K. Julien J.-P. Gros-Louis F. Caroni P. Neuron. 2013; 80 (this issue): 80-96Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar now provide evidence that moderate levels of glutamate receptor activation can counteract neurodegenerative processes in SOD1 ALS mouse models. Pharmacological inhibition of AMPA and NMDA receptors in transgenic mice overexpressing wild-type human SOD1 (these mice usually develop only mild MN pathology late in life) resulted in endoplasmic reticulum (ER) stress and accumulation of misfolded SOD1 in MNs. Conversely, treatment with AMPA reduced SOD1 accumulation. ER stress induced by tunicamycin or thapsigargin was sufficient to cause the selective accumulation of SOD1 aggregates in MNs of mutSOD1 mice but not in other neuronal populations examined. Thus, MNs in mutSOD1 mice are exceptionally vulnerable to ER stress, and its consequences can be mitigated by moderate activation of glutamate receptors and exacerbated by glutamate receptor inhibition. Not all subpopulations of MNs are equally vulnerable to degeneration in ALS; larger MNs in the spinal cord typically degenerate early in the course of the disease, whereas smaller cranial MNs are relatively resistant. Differences in cellular Ca2+ handling systems and consequent vulnerability to excitotoxicity may contribute to selective MN vulnerability because MNs with higher levels of Ca2+-binding proteins (CBPs) such as calbindin, parvalbumin, and the ER CBP calteticulin are more resistant than MNs with low levels of these CBPs (Bernard-Marissal et al., 2012Bernard-Marissal N. Moumen A. Sunyach C. Pellegrino C. Dudley K. Henderson C.E. Raoul C. Pettmann B. J. Neurosci. 2012; 32: 4901-4912Crossref PubMed Google Scholar). Differences in the expression or function of glutamate and GABA receptors, glial glutamate transporters, mitochondrial proteins, and ER stress and Ca2+-regulating proteins also affect MN vulnerability (Boillée et al., 2006Boillée S. Vande Velde C. Cleveland D.W. Neuron. 2006; 52: 39-59Abstract Full Text Full Text PDF PubMed Scopus (1139) Google Scholar). In mutSOD1 mice, fast fatiguing (FF) MNs with low excitability that innervate hind leg muscles succumb first, followed by medium excitability fatigue-resistant MNs; highly excitable MNs are relatively resistant. Saxena et al., 2013Saxena S. Roselli F. Singh K. Leptien K. Julien J.-P. Gros-Louis F. Caroni P. Neuron. 2013; 80 (this issue): 80-96Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar found that CNQX accelerated muscle denervation and death of mutSOD1 mice but had no discernible effects in transgenic mice expressing wild-type SOD1. AMPA treatment significantly delayed MN degeneration and extended survival of mutSOD1 mice. However, whereas fatigue-resistant MNs and highly excitable MNs were protected by AMPA, FF MNs were not substantially protected, indicating that AMPA receptor activation is less beneficial for the most vulnerable MNs. To determine whether direct activation of MNs enhances their resistance to mutant SOD1, Saxena et al., 2013Saxena S. Roselli F. Singh K. Leptien K. Julien J.-P. Gros-Louis F. Caroni P. Neuron. 2013; 80 (this issue): 80-96Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar employed pharmacologically selective actuator module (PSAM) technology to depolarize or hyperpolarize only MNs in mutSOD1 mice. This was accomplished using adeno-associated virus vectors to express the 5HT3 receptor (depolarization) or glycine receptor (hyperpolarization) in either MNs or parvalbumin-expressing interneurons on one side of the spinal cord. They found that under conditions expected to increase MN excitability, amounts of aggregated SOD1 and GRP78/Bip were reduced in the MNs, suggesting reduced ER stress. At first blush, the new findings (Saxena et al., 2013Saxena S. Roselli F. Singh K. Leptien K. Julien J.-P. Gros-Louis F. Caroni P. Neuron. 2013; 80 (this issue): 80-96Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar) appear to directly contradict the excitotoxicity hypothesis of ALS. MNs are vulnerable to AMPA receptor-mediated excitotoxicity and mutSOD1 increases the vulnerability of MNs to excitotoxicity by inducing oxidative stress and mitochondrial dysfunction and by impairing glutamate transport in astrocytes (Kruman et al., 1999Kruman I.I. Pedersen W.A. Springer J.E. Mattson M.P. Exp. Neurol. 1999; 160: 28-39Crossref PubMed Scopus (214) Google Scholar, Boillée et al., 2006Boillée S. Vande Velde C. Cleveland D.W. Neuron. 2006; 52: 39-59Abstract Full Text Full Text PDF PubMed Scopus (1139) Google Scholar). Moreover, intrathecal infusion of a blocker of Ca2+-permeable AMPA channels can retard MN degeneration in rats expressing mutant SOD1 (Yin et al., 2007Yin H.Z. Tang D.T. Weiss J.H. Exp. Neurol. 2007; 207: 177-185Crossref PubMed Scopus (36) Google Scholar). However, many biological systems exhibit a biphasic dose response to environmental stimuli, such that low levels of exposure are beneficial, whereas high levels of exposure are damaging, a phenomenon called hormesis that could explain both the ability of AMPA receptor activation to protect MNs (Saxena et al., 2013Saxena S. Roselli F. Singh K. Leptien K. Julien J.-P. Gros-Louis F. Caroni P. Neuron. 2013; 80 (this issue): 80-96Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar) and an excitotoxic mechanism of MN death in ALS (Figure 1). Indeed, activation of kinases and transcription factors such as CREB and NF-κB by the Ca2+ influx resulting from synaptic glutamate receptor activation can upregulate neurotrophic factors, Ca2+ handling proteins, antioxidant systems, protein chaperones, and DNA repair enzymes (Stranahan and Mattson, 2012Stranahan A.M. Mattson M.P. Nat. Rev. Neurosci. 2012; 13: 209-216PubMed Google Scholar). Calreticulin plays an important role in “sensing” ER Ca2+ levels and is a protein chaperone that can protect cells against ER stress. Saxena et al., 2013Saxena S. Roselli F. Singh K. Leptien K. Julien J.-P. Gros-Louis F. Caroni P. Neuron. 2013; 80 (this issue): 80-96Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar found that levels of calreticulin were reduced in MNs of mutSOD1 mice and that AMPA receptor activation increased calreticulin levels. Three other cellular stress response proteins that were affected by AMPA receptor activation and inhibition in MNs of mutSOD1 mice were GRP-78, DREAM/calsenilin, and GADD45b. GRP78 levels were elevated in mutant SOD1 MNs, and experimental enhancement of MN excitability reduced GRP78 levels, suggesting that excitation can reduce ER stress. However, GRP78 can protect neurons against excitotoxicity (Yu et al., 1999Yu Z. Luo H. Fu W. Mattson M.P. Exp. Neurol. 1999; 155: 302-314Crossref PubMed Scopus (407) Google Scholar) and so it might be expected that a reduction in GRP78 levels in response to AMPA receptor activation would increase the vulnerability of MNs to excitotoxicity. DREAM levels were reduced in MNs of mutSOD1 mice and AMPA receptor activation elevated DREAM levels (Saxena et al., 2013Saxena S. Roselli F. Singh K. Leptien K. Julien J.-P. Gros-Louis F. Caroni P. Neuron. 2013; 80 (this issue): 80-96Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). Elevation of DREAM levels in response to AMPA receptor activation may or may not be neuroprotective as DREAM can either protect against excitotoxicity or promote cell death, depending upon the cell type examined (Lilliehook et al., 2002Lilliehook C. Chan S. Choi E.K. Zaidi N.F. Wasco W. Mattson M.P. Buxbaum J.D. Mol. Cell. Neurosci. 2002; 19: 552-559Crossref PubMed Scopus (73) Google Scholar). Levels of GADD45b were elevated in MNs of FALS mice, and blockade of AMPA receptors reduced GADD45b levels, although it is not clear how these changes in GADD45b levels affect MN vulnerability. Thus, while AMPA receptor activation can modify several stress-responsive pathways, further work is required to establish which of these (or others not studied) mediate the neuroprotective effects of activity in mutSOD1 mice. The mammalian target of rapamycin (mTOR) protein plays a fundamental role in adjusting cell metabolism and growth to the availability of nutrients such as glucose and amino acids, which may be particularly important in MNs because of their large size and high metabolic demand. When energy and amino acids are plentiful, mTOR is active and stimulates protein synthesis. Activation of mTOR also reduces autophagy, a mechanism by which cells remove protein aggregates and damaged organelles by targeting them to lysosomes (Nixon, 2013Nixon R.A. Nat. Med. 2013; 19: 983-997Crossref PubMed Scopus (1334) Google Scholar). Inhibitors of mTOR such as rapamycin have recently been tested for their potential therapeutic application to a range of neurodegenerative disorders, with reported benefits in animal models of Huntington’s and Parkinson’s diseases (Sarkar et al., 2009Sarkar S. Ravikumar B. Floto R.A. Rubinsztein D.C. Cell Death Differ. 2009; 16: 46-56Crossref PubMed Scopus (433) Google Scholar). Similar to a previous study (Zhang et al., 2011Zhang X. Li L. Chen S. Yang D. Wang Y. Zhang X. Wang Z. Le W. Autophagy. 2011; 7: 412-425Crossref PubMed Scopus (287) Google Scholar), when Saxena et al., 2013Saxena S. Roselli F. Singh K. Leptien K. Julien J.-P. Gros-Louis F. Caroni P. Neuron. 2013; 80 (this issue): 80-96Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar treated mutSOD1 mice with rapamycin, the ALS disease process was exacerbated. Moreover, treatment of mutSOD1 mice with oxotremorine to stimulate mTOR and salubrinal to inhibit ER stress greatly slowed MN degeneration and extended survival of the mice. These and additional findings suggest that moderate levels of glutamate receptor activation can engage adaptive cellular stress response pathways that suppress mutant SOD aggregation and enhance mTOR-mediated protein synthesis to sustain MN survival. It remains to be determined whether enhancing activity in MNs can also counteract the pathogenic processes in more common forms of FALS not caused by an SOD1 mutation. In contrast to sporadic ALS and FALS caused by C9orf72 and TDP-43 mutations, MNs affected by SOD1 mutations do not exhibit TDP-43 pathology (Turner et al., 2013Turner M.R. Hardiman O. Benatar M. Brooks B.R. Chio A. de Carvalho M. Ince P.G. Lin C. Miller R.G. Mitsumoto H. et al.Lancet Neurol. 2013; 12: 310-322Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). Moreover, there is evidence that impaired autophagy may contribute to accumulation of TDP-43 in neurons (Wang et al., 2012Wang I.F. Guo B.S. Liu Y.C. Wu C.C. Yang C.H. Tsai K.J. Shen C.K. Proc. Natl. Acad. Sci. USA. 2012; 109: 15024-15029Crossref PubMed Scopus (299) Google Scholar) and that rapamycin can ameliorate such TDP-43 neuropathology (Caccamo et al., 2009Caccamo A. Majumder S. Deng J.J. Bai Y. Thornton F.B. Oddo S. J. Biol. Chem. 2009; 284: 27416-27424Crossref PubMed Scopus (128) Google Scholar). For reasons as yet unknown, MNs in the mutSOD1 mice appear not to be adversely affected when autophagy is downregulated by mTOR activation (Saxena et al., 2013Saxena S. Roselli F. Singh K. Leptien K. Julien J.-P. Gros-Louis F. Caroni P. Neuron. 2013; 80 (this issue): 80-96Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). Why might activation of mTOR be beneficial for MNs in mutSOD1 mice, while inhibition of mTOR is beneficial in several other neurodegenerative disorder models? One possibility is that MNs require higher levels of protein synthesis and can better tolerate reduced levels of autophagy compared to neurons affected in other neurodegenerative disorders. Finally, the new findings touch upon the practical issue of whether exercise/activity is beneficial or detrimental to MNs in the setting of ALS. Considerable evidence suggests that exercise stimulates neurotrophic factor production and is neuroprotective for some populations of neurons (Stranahan and Mattson, 2012Stranahan A.M. Mattson M.P. Nat. Rev. Neurosci. 2012; 13: 209-216PubMed Google Scholar). However, some epidemiological data suggest that elite athletes in sports that require extensive exertion are at increased risk for ALS. The hormesis paradigm provides a parsimonious explanation whereby moderate levels of MN excitation stimulates neurotrophic and protein biosynthetic pathways that protect against ALS, while higher levels of excitation may result in degeneration of the MNs, particularly in genetically predisposed individuals. Supported by the Intramural Research Program of the National Institute on Aging. Neuroprotection through Excitability and mTOR Required in ALS Motoneurons to Delay Disease and Extend SurvivalSaxena et al.NeuronOctober 02, 2013In BriefSaxena et al. show that in mouse models of familial motoneuron (MN) disease, disease-associated superoxide dismutase 1 (SOD1) mutants render vulnerable motoneurons dependent on endogenous neuroprotection involving excitability and mammalian target of Rapamycin (mTOR). Enhancing excitability signaling in motoneurons counteracts clinically important disease progression. Full-Text PDF Open Archive" @default.
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• W2011103525 title "Excitation BolsTORs Motor Neurons in ALS Mice" @default.
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