title: Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knock-out mice but predisposes neurons to oxidative stress.
abstract: 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.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. caih@mail.nih.gov
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
authors.forename: Xian
authors.initials: X
authors.lastname: Lin
authors.forename: Chengsong
authors.initials: C
authors.lastname: Xie
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Laird
authors.forename: Chen
authors.initials: C
authors.lastname: Lai
authors.forename: Hongjin
authors.initials: H
authors.lastname: Wen
authors.forename: Hsueh-Cheng
authors.initials: HC
authors.lastname: Chiang
authors.forename: Hoon
authors.initials: H
authors.lastname: Shim
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Farah
authors.forename: Ahmet
authors.initials: A
authors.lastname: Hoke
authors.forename: Donald L
authors.initials: DL
authors.lastname: Price
authors.forename: Philip C
authors.initials: PC
authors.lastname: Wong
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D002478:Cells, Cultured; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism*; D009048:Motor Skills / Q000502:physiology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*
chemical_list: C438187:ALS2 protein, human; D020662:Guanine Nucleotide Exchange Factors