Alsin and the molecular pathways of amyotrophic lateral sclerosis

Abstract

Autosomal recessive mutations in the ALS2 gene lead to a clinical spectrum of motor dysfunction including juvenile onset amyotrophic lateral sclerosis (ALS2), primary lateral sclerosis, and hereditary spastic paraplegia. The 184-kDa alsin protein, encoded by the full-length ALS2 gene, contains three different guanine-nucleotide-exchange factor-like domains, which may play a role in the etiology of the disease. Multiple in vitro biochemical and cell biology assays suggest that alsin dysfunction affects endosome trafficking through a Rab5 small GTPase family-mediated mechanism. Four ALS2-deficient mouse models have been generated by different groups and used to study the behavioral and pathological impact of alsin deficiency. These mouse models largely fail to recapitulate hallmarks of motor neuron disease, but the subtle deficits that are observed in behavior and pathology have aided in our understanding of the relationship between alsin and motor dysfunction. In this review, we summarize recent clinical and molecular reports regarding alsin and attempt to place these results within the larger context of motor neuron disease.

Fig. 1

Domain structures of alsin. a A schematic presentation of linear structure of full-length alsin and 3D structure models of predicated alsin functional domains. b 3D models of alsin RLD domain marked with two missense mutations, C156Y and G540E (I a top view, and II a side view). The mutation C156Y is located on a beta-strand in one of blade repeats close to the Ran-binding site. C156Y may break the blade and beta-propeller structure due to the bigger size of Tyr side-chain compared with the side-chain of Cys. That may cause the instability of mutant protein and may weaken or lose the binding between RCC1 and Ran. In addition to the side-chain collision, change of the non-polar Cys to polar Tyr may also cause the some polar changes in the hydrophobic core. The mutation G540E is located at the molecular surface. Glu is an acidic polar amino acid with big side-chain. Gly is a hydrophobic non-polar amino acid without side-chain. This change may affect the water network around the molecular surface. This mutation is not on the two binding sites, so it may not affect the interaction of alsin RLD with other molecules