Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Carter, Barrie J.; Anklesaria, Pervin; Choi, Stephanie; Engelhardt, John F.

doi:10.1089/ars.2008.2414

Cited by 36 publications

(35 citation statements)

References 145 publications

(245 reference statements)

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“…A recent genomewide association study in sporadic ALS patients has begun to shed light on this topic (18). Several genes that regulate endosomal trafficking, Rac1, and NADPH oxidases were identified in this study, including Nox4, TIAM2, IQGAP2, PTPRT, RAP1GAP, and MAGI2 (12). Interestingly, the ALS2 gene product alsin, which when mutated causes juvenile ALS, has also been shown to influence endosomal trafficking and Rac1 activity (19 -23).…”

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confidence: 73%

“…It has been hypothesized that alsin could potentially regulate Nox activity like SOD1 (12), but no direct information on this exists to date. We therefore sought to investigate whether alsin expression influences Nox-dependent ROS production in glial cells.…”

Section: Alsin Modulates Ros Production By Sod1mentioning

confidence: 99%

“…Excessive inflammation in ALS has been thought to involve amplification of a proinflammatory state exacerbated by excessive Nox-dependent ROS production (4,12). This interplay likely involves dysregulated production of inflammatory cytokines and neurotrophic factors that act in both a paracrine and autocrine fashion between activated microglia, activated astrocytes, and motor neurons.…”

Section: G93amentioning

confidence: 99%

“…Alsin appears to serve as a GEF for Rab5 and an effector of Rac1 GTPase activity (24 -26). These findings are of considerable interest because SOD1 also regulates Rac1 GTPase and NADPH oxidase activity in Rab5-bound early endosomes (7,8,11,12). Both the Rab5-GEF and Rac1-effector functions of alsin appear to influence endocytic mechanisms and endosomal dynamics (20,26) and alsin appears to protect from motor neuron degeneration in certain SOD1 mutant mice (20) and motor neurons expressing SOD1 mutants in culture (27,28).…”

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confidence: 98%

“…ROS produced by the redoxosome facilitate the redox-dependent recruitment of TRAFs to TNFR1 and IL-1R1 and in this manner facilitate proinflammatory signaling such as NFB activation (8 -11). Interestingly, mutant forms of SOD1 have enhanced redox-independent binding to Rac1 and this has been proposed as a mechanism for enhanced ROS production in microglia of ALS mice (7,12).…”

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confidence: 99%

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Alsin and SOD1G93A Proteins Regulate Endosomal Reactive Oxygen Species Production by Glial Cells and Proinflammatory Pathways Responsible for Neurotoxicity

Spencer

Pantazis

et al. 2011

Journal of Biological Chemistry

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Recent studies have implicated enhanced Nox2-mediated reactive oxygen species (ROS) by microglia in the pathogenesis of motor neuron death observed in familial amyotrophic lateral sclerosis (ALS). In this context, ALS mutant forms of SOD1 enhance Rac1 activation, leading to increased Nox2-dependent microglial ROS production and neuron cell death in mice. It remains unclear if other genetic mutations that cause ALS also function through similar Nox-dependent pathways to enhance ROS-mediate motor neuron death. In the present study, we sought to understand whether alsin, which is mutated in an inherited juvenile form of ALS, functionally converges on Rac1-dependent pathways acted upon by SOD1G93A to regulate Noxdependent ROS production. Our studies demonstrate that glial cell expression of SOD1 G93A or wild type alsin induces ROS production, Rac1 activation, secretion of TNF␣, and activation of NFB, leading to decreased motor neuron survival in co-culture. Interestingly, coexpression of alsin, or shRNA against Nox2, with SOD1 G93A in glial cells attenuated these proinflammatory indicators and protected motor neurons in co-culture, although shRNAs against Nox1 and Nox4 had little effect. SOD1G93A expression dramatically enhanced TNF␣-mediated endosomal ROS in glial cells in a Rac1-dependent manner and alsin overexpression inhibited SOD1 G93A -induced endosomal ROS and Rac1 activation. SOD1 G93A expression enhanced recruitment of alsin to the endomembrane compartment in glial cells, suggesting that these two proteins act to modulate Nox2-dependent endosomal ROS and proinflammatory signals that modulate NFB. These studies suggest that glial proinflammatory signals regulated by endosomal ROS are influenced by two gene products known to cause ALS.Amyotrophic lateral sclerosis (ALS) is a lethal degenerative neurological disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord (1, 2). The majority of ALS patients have onset of disease between 40 and 50 years of age and about 50% of patients die within 3 years. The majority of ALS cases are categorized as sporadic with no family history of disease. In this context, the causative genes and environmental factors that initiate the disease process remain poorly defined. Only ϳ10% of ALS cases have a clearly inherited genetic component and hence are classified as familial ALS (1, 2).The best-characterized forms of familial ALS include those caused by mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1) 2 (3). Approximately 20% of familial ALS cases are caused by a variety of dominant SOD1 mutations (1, 3). There remains great uncertainty as to the primary mechanism(s) by which mutant SOD1 leads to pathology observed in ALS (1, 4). Proposed mechanisms include toxicity associated with misfolding of mutant SOD1, such as ER stress and inhibition of the proteasome, enhanced proinflammatory ROS production, altered axonal transport, excitotoxicity caused by glutamate mishandling, and mitochondrial damage (1, 4). Relevant to the studi...

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mentioning

confidence: 73%

Section: Alsin Modulates Ros Production By Sod1mentioning

confidence: 99%

Section: G93amentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

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Alsin and SOD1G93A Proteins Regulate Endosomal Reactive Oxygen Species Production by Glial Cells and Proinflammatory Pathways Responsible for Neurotoxicity

Spencer

Pantazis

et al. 2011

Journal of Biological Chemistry

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MicroRNA-338 regulates the axonal expression of multiple nuclear-encoded mitochondrial mRNAs encoding subunits of the oxidative phosphorylation machinery

Aschrafi

Kar

Natera-Naranjo

et al. 2012

Cell. Mol. Life Sci.

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MicroRNAs (miRNAs) constitute a novel class of small, non-coding RNAs that act as post-transcriptional regulators of gene expression. Remarkably, it has been shown that these small molecules can coordinately regulate multiple genes coding for proteins with related cellular functions. Previously, we reported that brain-specific miR-338 modulates the axonal expression of cytochrome c oxidase IV (COXIV), a nuclear-encoded mitochondrial protein that plays a key role in oxidative phosphorylation and axonal function. Here, we report that ATP synthase (ATP5G1), like COXIV mRNA, contains a putative miR-338 binding site, and that modulation of miR-338 levels in the axon results in alterations in both COXIV and ATP5G1 expression. Importantly, miR-338 modulation of local COXIV and ATP5G1 expression has a marked effect on axonal ROS levels, as well as axonal growth. These findings point to a mechanism by which miR-338 modulates local energy metabolism through the coordinate regulation of the expression of multiple nuclear-encoded mitochondrial mRNAs in the axon.

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Mitochondrial Dysfunction and Molecular Bases of Neurodegenerative Diseases

Колесникова

2013

Neurophysiology

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Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

Cited by 36 publications

References 145 publications

Alsin and SOD1G93A Proteins Regulate Endosomal Reactive Oxygen Species Production by Glial Cells and Proinflammatory Pathways Responsible for Neurotoxicity

Alsin and SOD1G93A Proteins Regulate Endosomal Reactive Oxygen Species Production by Glial Cells and Proinflammatory Pathways Responsible for Neurotoxicity

MicroRNA-338 regulates the axonal expression of multiple nuclear-encoded mitochondrial mRNAs encoding subunits of the oxidative phosphorylation machinery

Mitochondrial Dysfunction and Molecular Bases of Neurodegenerative Diseases

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