Loss of ALS2 Function Is Insufficient to Trigger Motor Neuron Degeneration in Knock-Out Mice But Predisposes Neurons to Oxidative Stress

Johns Hopkins University, Baltimore, Maryland, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 09/2005; 25(33):7567-74. DOI: 10.1523/JNEUROSCI.1645-05.2005
Source: PubMed


Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is caused by a selective loss of motor neurons in the CNS. Mutations in the ALS2 gene have been linked to one form of autosomal recessive juvenile onset ALS (ALS2). To investigate the pathogenic mechanisms of ALS2, we generated ALS2 knock-out (ALS2(-/-)) mice. Although ALS2(-/-) mice lacked obvious developmental abnormalities, they exhibited age-dependent deficits in motor coordination and motor learning. Moreover, ALS2(-/-) mice showed a higher anxiety response in the open-field and elevated plus-maze tasks. Although they failed to recapitulate clinical or neuropathological phenotypes consistent with motor neuron disease by 20 months of age, ALS2(-/-) mice or primary cultured neurons derived from these mice were more susceptible to oxidative stress compared with wild-type controls. These observations suggest that loss of ALS2 function is insufficient to cause major motor deficits or motor neuron degeneration in a mouse model but predisposes neurons to oxidative stress.


Available from: Chen Lai, Feb 17, 2014
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    • "However, it has been reported that ALS2 KO mice develop age-dependent deficits in motor coordination (Cai et al., 2005), an age-dependent and slow progressive loss of cerebellar Purkinje cells, a reduction in ventral motor axons during aging, astrogliosis, and evidence of deficits in endosome trafficking (Hadano et al., 2006), degeneration of corticospinal axons and axonal transport defects (Gros-Louis et al., 2008). In addition, primary cultured motor neurons lacking ALS2 have been found to be more susceptible to oxidative stress (Cai et al., 2005). "
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    ABSTRACT: Small GTPases participate in a broad range of cellular processes such as proliferation, differentiation, and migration. The exchange of GDP for GTP resulting in the activation of these GTPases is catalyzed by a group of enzymes called guanine nucleotide exchange factors (GEFs), of which two classes: Dbl-related exchange factors and the more recently described dedicator of cytokinesis proteins family exchange factors. Increasingly, deregulation of normal GEF activity or function has been associated with a broad range of disease states, including neurodegeneration and neurodevelopmental disorders. In this review, we examine this evidence with special emphasis on the novel role of Rho guanine nucleotide exchange factor (RGNEF/p190RhoGEF) in the pathogenesis of amyotrophic lateral sclerosis. RGNEF is the first neurodegeneration-linked GEF that regulates not only RhoA GTPase activation but also functions as an RNA binding protein that directly acts with low molecular weight neurofilament mRNA 3' untranslated region to regulate its stability. This dual role for RGNEF, coupled with the increasing understanding of the key role for GEFs in modulating the GTPase function in cell survival suggests a prominent role for GEFs in mediating a critical balance between cytotoxicity and neuroprotection which, when disturbed, contributes to neuronal loss.
    Frontiers in Cellular Neuroscience 09/2014; 8. DOI:10.3389/fncel.2014.00282 · 4.29 Impact Factor
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    • "In particular, fusion between early endosomes and macropinosomes is, at least in part, regulated by ALS2 in an ALS2-associated Rab5 GEF activity-dependent manner [124]. Further, ALS2 plays some modulatory roles in axonal outgrowth in neuronal cells [125, 126], and in cytoprotection from oxidative stress-induced insults [127–130]. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of incurable motor neuron diseases (MNDs) characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5-10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.
    Neurology Research International 07/2012; 2012(6415):498428. DOI:10.1155/2012/498428
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    • "l . , 2003 ; Hadano , et al . , 2001 ; Kress , et al . , 2005 ; Yang , et al . , 2001 ) . The pattern of inheritance and the nature of the mutations identified in this gene suggest that motor neuron degeneration seen in patients results from a loss of protein function . Six different groups have reported the generation of an alsin knockout mouse ( Cai , et al . , 2005 ; Deng , et al . , 2007 ; Devon , et al . , 2003 ; Gros - Louis , et al . , 2008 ; Hadano , et al . , 2006 ; Yamanaka , et al . , 2006 ) . Despite an age"
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    ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset neurodegenerative disorder characterized by the death of large motor neurons in the cerebral cortex and spinal cord (Tandan and Bradley, 1985). Dysfunction and death of these cell populations lead to progressive muscle weakness, atrophy, fasciculations, spasticity and ultimately, paralysis and death usually within 3 to 5 years after disease onset (Mulder, 1982). The estimated worldwide incidence for this disease is around 2 per 100,000 in the general population and the life-long risk to develop ALS is approximately 1:2000. The disease occurs in sporadic (90%) and familial forms (10%) (Gros-Louis, et al., 2006). With the exception of few FALS cases in which other neurodegenerative disorders can simultaneously occur, FALS and SALS are clinically indistinguishable. To date, mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene have remained the major known genetic causes associated with ALS. However, the mechanism whereby mutant SOD1 causes specific degeneration of motor neurons remains unclear. Nonetheless, many neuronal death pathways have been revealed through studies with transgenic mice expressing SOD1 mutants. Other vertebrate, invertebrate and in vitro models of ALS have also been described. Here, we will review various animal and cellular models that have been used to study the toxicity of ALS-linked gene mutations and also to investigate pathological hallmarks of the disease.
    AMYOTROPHIC LATERAL SCLEROSIS, Edited by Martin H Maurer, 01/2012: chapter In Vivo and In Vitro Models to Study Amyotrophic Lateral Sclerosis: pages 81-124; InTech., ISBN: 978-953-307-806-9
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