ALS: a disease of motor neurons and their nonneuronal neighbors.

Although Charcot described amyotrophic lateral sclerosis (ALS) more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in this common adult motor neuron disease has remained a mystery. There is no effective remedy for this progressive, fatal disorder. Modern genetics has now identified mutations in one gene [Cu/Zn superoxide dismutase (SOD1)] as a primary cause and implicated others [encoding neurofilaments, cytoplasmic dynein and its processivity factor dynactin, and vascular endothelial growth factor (VEGF)] as contributors to, or causes of, motor neuron diseases. These insights have enabled development of model systems to test hypotheses of disease mechanism and potential therapies. Along with errors in the handling of synaptic glutamate and the potential excitotoxic response this provokes, these model systems highlight the involvement of nonneuronal cells in disease progression and provide new therapeutic strategies.

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Unraveling the mechanisms involved in motor neuron degeneration in ALS.

Since its description by Charcot more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in amyotrophic lateral sclerosis has remained a mystery. Modern genetics has now identified mutations in two genes — SOD1 and ALS2 — as primary causes of the disease, and has implicated others as potential contributors. Insights into these abnormalities, together with errors in the handling of synaptic glutamate and the potential excitotoxic response that this alteration provokes, have provided leads for the development of new strategies to identify an as yet elusive remedy for this progressive, fatal disorder.

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From charcot to lou gehrig: deciphering selective motor neuron death in als

Rho GTPases control many aspects of cell behavior through the regulation of multiple signal transduction pathways (Van Aelst and D’Souza-Schorey 1997; Hall 1998). Rho, Rac, and Cdc42 were first recognized in the early 1990s for their unique ability to induce specific filamentous actin structures in fibroblasts; stress fibers, lamellipodia/membrane ruffles, and filopodia, respectively (Hall 1998). Over the intervening years, evidence has accumulated to show that in all eukaryotic cells, Rho GTPases are involved in most, if not all, actin-dependent processes such as those involved in migration, adhesion, morphogenesis, axon guidance, and phagocytosis (Kaibuchi et al. 1999; Chimini and Chavrier 2000; Luo 2000). In addition to their well-established roles in controlling the actin cytoskeleton, Rho GTPases regulate the microtubule cytoskeleton, cell polarity, gene expression, cell cycle progression, and membrane transport pathways (Van Aelst and D’Souza-Schorey 1997; Daub et al. 2001; Etienne-Manneville and Hall 2001). With such a prominent role in so many aspects of cell biology, it is not surprising that they are themselves highly regulated. Like all GTPases, Rho proteins act as binary switches by cycling between an inactive (GDP-bound) and an active (GTP-bound) conformational state (Fig. 1; Van Aelst and D’Souza-Schorey 1997). The cell controls this switch by regulating the interconversion and accessibility of these two forms in a variety of ways. Guanine nucleotide exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate the activated form, which is then capable of recognizing downstream targets, or effector proteins. GTPase activating proteins (GAPs) accelerate the intrinsic GTPase activity of Rho family members to inactivate the switch. Finally, guanine nucleotide dissociation inhibitors (GDIs) interact with the prenylated, GDP-bound form to control cycling between membranes and cytosol. In theory, activation of a Rho GTPase could occur through stimulation of a GEF or inhibition of a GAP. In practice, however, all the evidence points to GEFs being the critical mediators of Rho GTPase activation, and this paper reviews our present understanding of how they do this. Structural features

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Guanine nucleotide exchange factors for Rho GTPases: turning on the switch

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by motor neuron degeneration. Mutations in more than 50 human genes cause diverse types of motor neuron pathology. Moreover, defects in five Mendelian genes lead to motor neuron disease, with two mutations reproducing the ALS phenotype. Analyses of these genetic effects have generated new insights into the diverse molecular pathways involved in ALS pathogenesis. Here, we present an overview of the mechanisms for motor neuron death and of the role of non-neuronal cells in ALS.

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Molecular biology of amyotrophic lateral sclerosis: insights from genetics.

Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs).

The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.

Toru Sasaki

Papers

The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.