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.

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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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    • "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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    • "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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