A Rac1/Phosphatidylinositol 3-Kinase/Akt3 Anti-apoptotic Pathway, Triggered by AlsinLF, the Product of the ALS2 Gene, Antagonizes Cu/Zn-superoxide Dismutase (SOD1) Mutant-induced Motoneuronal Cell Death

Kanekura, Kohsuke; Hashimoto, Yuichi; Kita, Yoshiko; Sasabe, Jumpei; Aiso, Sadakazu; Nishimoto, Ikuo; Matsuoka, Masao

doi:10.1074/jbc.m410508200

Cited by 96 publications

(91 citation statements)

References 58 publications

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“…Based on previously reported in vitro data that ALS2 plays a protective role against mutant SOD1-mediated toxicity [7], we hypothesized that SOD1 G93A / ALS2 −/− mice would exhibit a shorter life span and display more severe motor neuron degeneration compared with SOD1 G93A /ALS2 +/+ mice. Surprisingly, we did not observe any obvious effects of the loss of ALS2 gene on motor neuron degeneration or survival of SOD1 G93A transgenic mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we and others have generated ALS2 knockout (ALS2 −/− ) mice that failed to display any obvious motor neuron degeneration [1,4]. Since over-expression of ALS2 protects cells from SOD1-mediated cytotoxicity and loss of ALS2 predisposes neurons to paraquat-induced oxidative stress [1,7], ALS2 may serve as a risk factor for motor neuron disease. In this study, we examined whether the deficiency in the ALS2 gene affected the well-characterized motor neuron degeneration in SOD1 G93A transgenic mice [3].…”

Section: Introductionmentioning

confidence: 99%

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Deficiency in the ALS2 gene does not affect the motor neuron degeneration in SOD1G93A transgenic mice

Lin

Shim

Cai

2007

Neurobiology of Aging

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Dysfunction of the ALS2 gene has been linked to one form of juvenile onset autosomal recessive amyotrophic lateral sclerosis (ALS). Previous in vitro studies suggest that over-expression of ALS2 protects cells from mutant Cu/Zn superoxide dismutase (SOD1)-induced cytotoxicity. To test whether ALS2 plays a protective role against mutant SOD1-mediated motor neuron degeneration in vivo, we examined the progression of motor neuron disease in SOD1 G93A mice on an ALS2 null background. Our data suggest that deficiency in the ALS2 gene does not affect the pathogenesis of SOD1 G93A mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deficiency in the ALS2 gene does not affect the motor neuron degeneration in SOD1G93A transgenic mice

Lin

Shim

Cai

2007

Neurobiology of Aging

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“…It contains 3 putative GEF domains: an amino-terminal domain that displays homology to the Ran GEF RCC1; a central region containing Dbl and pleckstrin homology (DH/PH) domain that is present in GEFs for Rho, Rac and Cdc42; and a carboxyl-terminal vacuolar protein-sorting 9 (VPS9) domain that is found in GEFs for Rab5. Subsequent studies have indeed demonstrated that alsin acts in vitro as a GEF for Rab5 and Rac1 [43,63,80,81]. At present, it is very unclear how the Rac1 and Rab5 exchange activities of alsin influence motor neuron maintenance and survival and contribute to the disease of ALS.…”

Section: Alsinmentioning

confidence: 99%

“…With respect to alsin's role as a Rho family GEF, experiments have shown that alsin is an exchange factor for Rac1 [43,80,81]. Alsin specifically interacts with Rac1 and shows little, if any, association with Rac3, RhoA, or Cdc42.…”

Section: Alsinmentioning

confidence: 99%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3 % of children and young adults. MR has been consistently associated with changes in dendrites and dendritic spine structure. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to be the underlying cause of cognitive disabilities observed in MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore naturally attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. In support of this, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotropic lateral sclerosis (ALS). Here we will discuss Rho GTPase related genes and their signaling pathways involved in MR and ALS.

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“…8 We have independently shown that wild-type alsin suppresses mutant SOD1-induced neuronal cell death by activating a prosurvival pathway involving Rac1, PI3K and Akt3, and that FALS-linked mutations in the gene abolish the alsin function. 9,10 To further characterize the Akt-mediated prosurvival pathways that are linked to the ALS pathogenesis, we previously performed an yeast-two hybrid analysis and identified BTBD10 as an Akt3-binding protein. BTBD10 activates Akt by inhibiting PP2A-mediated Akt dephosphorylation and inactivation.…”

mentioning

confidence: 99%

Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

et al. 2012

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BTBD10, an Akt interactor, activates Akt by decreasing the protein phosphatase 2A-mediated dephosphorylation and inactivation of Akt. Overexpression of BTBD10 suppresses motor neuron death that is induced by a familial amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 (SOD1) mutant, G93A-SOD1 in vitro. In this study, we further investigated the BTBD10-mediated suppression of motor neuron death. We found that the small interfering RNA-mediated inhibition of BTBD10 expression led to the death of cultured motor neurons. In Caenorhabditis elegans (C. elegans), disruption of the btbd-10 gene caused not only loss of neurons, including both motor and touch-receptor neurons, but also a locomotion defect. In addition, we found that the expression of BTBD10 was generally decreased in the motor neurons from patients of sporadic ALS and transgenic mice overexpressing G93A-SOD1 (G93A-SOD1-transgenic mice). Collectively, these results suggest that the reduced expression of BTBD10 leads to motor neuron death both in vitro and in vivo. A gain-of-toxic-function of an intracellular molecule or a loss of normal function of an essential intracellular molecule, including an intracellular prosurvival signal, contributes to cell death. The Akt family of proteins (Akt1, 2 and 3 in mammalian cells) provides a major intracellular prosurvival signal by phosphorylating many target proteins. 1 The major upstream activator of Akt is the phosphatidylinositol 3-kinase (PI3K)-mediated signal that activates Akt by phosphorylation. Akt's activity is also regulated by protein phosphatase-mediated dephosphorylation. 2 In our previous study, we showed that BTBD10 activates Akt by inhibiting protein phosphatase 2A (PP2A)-mediated Akt dephosphorylation. 3 Recent advances in genetics and neuroscience have suggested that both gains of toxic and/or losses of normal function of intracellular molecules contribute to the pathogenesis of neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a representative motor neuron-specific neurodegenerative disease. 4 Approximately 10% of ALS cases are genetically inherited. 4,5 Dominant mutations in the superoxide dismutase 1 (SOD1) gene (the first identified familial ALS (FALS)-linked gene) account for approximately 20% of FALS cases. The gain-of-toxic-function of SOD1, caused by a FALS-linked mutation, is thought to be closely linked to the ALS pathogenesis. The second identified FALS-linked gene, a FALS-linked mutation of which results in an autosomal-recessive phenotype, encodes a protein named alsin. 6,7 Loss of alsin function, caused by a FALSlinked mutation, leads to the abnormal endolysosomal trafficking and contributes to motor neuron death. 8 We have independently shown that wild-type alsin suppresses mutant SOD1-induced neuronal cell death by activating a prosurvival pathway involving Rac1, PI3K and Akt3, and that FALS-linked mutations in the gene abolish the alsin function. 9,10 To further characterize the Akt-mediated prosurvival pathways that are linked to the ALS pathogenesi...

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A Rac1/Phosphatidylinositol 3-Kinase/Akt3 Anti-apoptotic Pathway, Triggered by AlsinLF, the Product of the ALS2 Gene, Antagonizes Cu/Zn-superoxide Dismutase (SOD1) Mutant-induced Motoneuronal Cell Death

Cited by 96 publications

References 58 publications

Deficiency in the ALS2 gene does not affect the motor neuron degeneration in SOD1G93A transgenic mice

Deficiency in the ALS2 gene does not affect the motor neuron degeneration in SOD1G93A transgenic mice

Rho-linked genes and neurological disorders

Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

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