ALS2/alsin deficiency in neurons leads to mild defects in macropinocytosis and axonal growth

Otomo, Asako; Kunita, Ryota; Suzuki-Utsunomiya, Kyoko; Mizumura, Hikaru; Onoe, Kyuichiro; Osuga, Hitoshi; Hadano, Shinji; Ikeda, Joh‐E

doi:10.1016/j.bbrc.2008.01.177

Cited by 38 publications

(33 citation statements)

References 25 publications

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“…The mutation of this gene leads to juvenile onset of slowly progressive MN disease in humans 71,72 and a mild phenotype in mice. 70 Even this alteration is concomitant with an increase in autophagy markers.…”

Section: Role Of Autophagy In Specific Genetic Forms Of Mn Deathmentioning

confidence: 98%

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Autophagy, lithium, and amyotrophic lateral sclerosis

et al. 2009

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In this article we provide an overview of the intersection between amyotrophic lateral sclerosis (ALS) and the autophagy pathway and discuss the potential protective effects of lithium through mechanisms that recruit autophagy and other effects. The autophagy pathway is recruited during motor neuron (MN) death both in vitro and in vivo. Despite a few controversial issues concerning the significance (detrimental/protective) of autophagy in ALS, recent findings indicate a protective role. Lithium in low doses is a well-known autophagy inducer that clears misfolded proteins and altered mitochondria from MNs. Moreover, lithium preserves mitochondria and sustains their genesis. This effect is replicated by rapamycin, which is an autophagy inducer but with a different mechanism from lithium. Lithium also increases the number of Renshaw cells that are affected early during the progression of experimental ALS. Again, lithium has been reported to decrease glial proliferation in the ALS spinal cord and induces sprouting in corticospinal fibers. Muscle Nerve 40: 173-194, 2009.

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Section: Role Of Autophagy In Specific Genetic Forms Of Mn Deathmentioning

confidence: 98%

“…ALS2/Alsin, promotes the dynamics of endosomes within the cells (Figs. 3, 5) and has been implicated as an autophagy-like process (macropynocytosis 69,70 ). The mutation of this gene leads to juvenile onset of slowly progressive MN disease in humans 71,72 and a mild phenotype in mice.…”

Section: Role Of Autophagy In Specific Genetic Forms Of Mn Deathmentioning

confidence: 99%

Autophagy, lithium, and amyotrophic lateral sclerosis

et al. 2009

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“…Alsin is also an effector of Rac1 that has been shown to control endocytic mechanisms at the cell membrane (26,52) and endolysosomal trafficking (20). Thus, alsin is a key regulator of endosomal dynamics.…”

Section: Discussionmentioning

confidence: 99%

Alsin and SOD1G93A Proteins Regulate Endosomal Reactive Oxygen Species Production by Glial Cells and Proinflammatory Pathways Responsible for Neurotoxicity

Spencer

Pantazis

et al. 2011

Journal of Biological Chemistry

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Recent studies have implicated enhanced Nox2-mediated reactive oxygen species (ROS) by microglia in the pathogenesis of motor neuron death observed in familial amyotrophic lateral sclerosis (ALS). In this context, ALS mutant forms of SOD1 enhance Rac1 activation, leading to increased Nox2-dependent microglial ROS production and neuron cell death in mice. It remains unclear if other genetic mutations that cause ALS also function through similar Nox-dependent pathways to enhance ROS-mediate motor neuron death. In the present study, we sought to understand whether alsin, which is mutated in an inherited juvenile form of ALS, functionally converges on Rac1-dependent pathways acted upon by SOD1G93A to regulate Noxdependent ROS production. Our studies demonstrate that glial cell expression of SOD1 G93A or wild type alsin induces ROS production, Rac1 activation, secretion of TNF␣, and activation of NFB, leading to decreased motor neuron survival in co-culture. Interestingly, coexpression of alsin, or shRNA against Nox2, with SOD1 G93A in glial cells attenuated these proinflammatory indicators and protected motor neurons in co-culture, although shRNAs against Nox1 and Nox4 had little effect. SOD1G93A expression dramatically enhanced TNF␣-mediated endosomal ROS in glial cells in a Rac1-dependent manner and alsin overexpression inhibited SOD1 G93A -induced endosomal ROS and Rac1 activation. SOD1 G93A expression enhanced recruitment of alsin to the endomembrane compartment in glial cells, suggesting that these two proteins act to modulate Nox2-dependent endosomal ROS and proinflammatory signals that modulate NFB. These studies suggest that glial proinflammatory signals regulated by endosomal ROS are influenced by two gene products known to cause ALS.Amyotrophic lateral sclerosis (ALS) is a lethal degenerative neurological disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord (1, 2). The majority of ALS patients have onset of disease between 40 and 50 years of age and about 50% of patients die within 3 years. The majority of ALS cases are categorized as sporadic with no family history of disease. In this context, the causative genes and environmental factors that initiate the disease process remain poorly defined. Only ϳ10% of ALS cases have a clearly inherited genetic component and hence are classified as familial ALS (1, 2).The best-characterized forms of familial ALS include those caused by mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1) 2 (3). Approximately 20% of familial ALS cases are caused by a variety of dominant SOD1 mutations (1, 3). There remains great uncertainty as to the primary mechanism(s) by which mutant SOD1 leads to pathology observed in ALS (1, 4). Proposed mechanisms include toxicity associated with misfolding of mutant SOD1, such as ER stress and inhibition of the proteasome, enhanced proinflammatory ROS production, altered axonal transport, excitotoxicity caused by glutamate mishandling, and mitochondrial damage (1, 4). Relevant to the studi...

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“…67 Small GTPases control a broad spectrum of cellular and molecular processes, including chromatin condensation, 69 regulation of actin cytoskeleton organization, 70 signaling cascades, 71 neuronal morphogenesis, 72,73 axonal/ neurite growth, and neuroprotection processes. [74][75][76] Although deletions and mutations in the coding sequence of ALS2 are involved in a juvenile recessive form of amyotrophic lateral sclerosis, 39,40 recent data suggest that this gene is also associated with psychiatric phenotypes. 77 Indeed, loss of ALS2 function is associated with behavioral alterations related to anxietylike phenotypes.…”

Section: Commentmentioning

confidence: 99%