Loss ofALS2Function 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 Ϫ/Ϫ ) mice. Although ALS2 Ϫ/Ϫ mice lacked obvious developmental abnormalities, they exhibited age-dependent deficits in motor coordination and motor learning. Moreover, ALS2Ϫ/Ϫ 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 Ϫ/Ϫ 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.

Rho-linked genes and neurological disorders

“…Consistent with these observations, Devon et al showed that Als2 -/-mice reveal Rab5-dependent fusion of early endosomes, and a disturbance in endosomal transport of insuline-like growth factor 1 and brain-derived neurotrophic factor receptors [19]. Surprisingly, these Als2 -/-mice did not show any obvious clinical, histopathological, or electrophysiological signs of neuronal degeneration [12,19,34]. The latter could be due to compensations during development.…”

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

“…The generation of ALS2 −/− mice, rotarod test and histological analysis were conducted as previously described [1]. Survival data were analyzed using a log-rank test and statistical significant differences were at a minimal level of significance of p < 0.05.…”

“…Recently, mutations in a second ALS-related gene (ALS2) were identified that cause a rare recessive form of juvenile onset ALS [5,9]. 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.…”

“…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].…”

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

“…These include: an N-terminal regulator of chromatin condensation (RCC1)-like domain, which resembles the GEF for the Ran GTPase; a middle Dbl homology (DH)-and pleckstrin homology (PH)-like domain similar to the GEF for Rho GTPase; and a Cterminal vacuolar protein sorting 9 (VPS9)-like domain that is homologous to the Rab GTPase GEF (26,54). The exact mechanism by which mutations in ALS2 lead to ALS-like disease remains unknown, and this is confounded by the fact that motor neuron degeneration is not observed in ASL2 knockout mice (23). Interestingly, however, ALS2 knockout mice do have increased susceptibility to paraquat-induced neuronal oxidative stress (23), lymphopenia and hematopoiesis abnormalities (40), and endosome trafficking defects (34).…”