Als2 -deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities

Abstract

ALS2 is an autosomal recessive form of spastic paraparesis (motor neuron disease) with juvenile onset and slow progression caused by loss of function of alsin, an activator of Rac1 and Rab5 small GTPases. To establish an animal model of ALS2 and derive insights into the pathogenesis of this illness, we have generated alsin-null mice. Cytosol from brains of Als2 ؊/؊ mice shows marked diminution of Rab5-dependent endosome fusion activity. Furthermore, primary neurons from Als2 ؊/؊ mice show a disturbance in endosomal transport of insulin-like growth factor 1 (IGF1) and BDNF receptors, whereas neuronal viability and endocytosis of transferrin and dextran seem unaltered. There is a significant decrease in the size of cortical motor neurons, and Als2 ؊/؊ mice are mildly hypoactive. Altered trophic receptor trafficking in neurons of Als2 ؊/؊ mice may underlie the histopathological and behavioral changes observed and the pathogenesis of ALS2.ALS ͉ alsin ͉ knockout mouse ͉ motor neuron ͉ Rab5

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.…”

“…Hadano et al reported that alsin knock-out mice exhibit a slowly, but progressive, loss of cerebellar Purkinje cells, together with a subclinical motor dysfunction and altered endosome trafficking [34]. 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].…”

Action in the axon: generation and transport of signaling endosomes

“…Axo-terminal degeneration of motor neurons also occurs in mice with mutations in the p150 Glued subunit of dynactin, although it is unclear whether axonopathy arises from impaired retrograde transport or an alteration in protein degradation [40,41]. The juvenile ALSassociated gene ALS2, encoding the protein Alsin, seems to play a role in transport and axonal maintenance, as several lines of Alsin-deficient mice show variable defects in endosomal trafficking of growth factor and neurotrophin receptors, including epidermal growth factor (EGF), insulin-like growth factor (IGF), and BDNF receptors [46,47], and some lines of Alsindeficient mice also show axonal degeneration of motor neurons [48,49]. The pathology of these diseases suggests that retrograde transport may play a special role in maintaining axonal health.…”

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

“…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).…”

“…Whether Alsin's association with mutant SOD1 and=or Rac1 also mitigates hyperactivation of Nox2 in the endosomal compartment remains to be determined. Second, ALS2 knockout mice demonstrate an increased susceptibility to paraquat-induced neuronal oxidative stress (23) as well as defects in endosome trafficking (34). Hence, Alsin appears to protect cells from redox-stress while also influencing endosomal dynamics.…”