ALS2

ALS2 Full Name

amyotrophic lateral sclerosis 2 (juvenile)

ALS2 Introduction

ALS2 encodes alsin, a 1,657-amino-acid multidomain protein that functions as a guanine nucleotide exchange factor (GEF) for small GTPases of the Rab and Rho families. Alsin is broadly expressed, with highest levels in motor neurons of the spinal cord and brain. The protein contains an N-terminal regulator of chromosome condensation 1 (RCC1)–like domain, a central vacuolar protein sorting 9 (VPS9) domain that acts as a GEF for Rab5 on early endosomes, and a C-terminal moniker/PRS7 domain with GEF activity toward Rac1. Through these interactions, alsin orchestrates endosomal vesicle trafficking, actin cytoskeleton dynamics, and autophagy—processes that are collectively essential for axonal transport, neurite outgrowth, and neuronal survival. In motor neurons, alsin localizes to axonal growth cones and endosomal vesicles, where it coordinates the delivery of signaling endosomes required for long-range trophic support from the soma to the neuromuscular junction.

Figure 1. Alsin domains. (Source: Yang Y, et al. 2001)

Biallelic mutations in ALS2 cause a spectrum of autosomal recessive motor neuron disorders with an early-onset, slowly progressive phenotype. The most common molecular defect is a deletion of exon 2, which generates a frameshift and premature stop codon, producing a truncated nonfunctional protein. The clinical entity most closely linked to ALS2 loss-of-function is juvenile recessive ALS (ALS2-AR), characterized by spastic paraparesis, progressive limb weakness and spasticity, bulbar dysfunction, and eventual generalized muscle atrophy, typically beginning in childhood or adolescence. Notably, the clinical phenotype of ALS2-mutant patients overlaps substantially with hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS), with some classification schemes grouping these conditions as part of a single ALS2-related disease spectrum. At the cellular level, loss of alsin GEF activity leads to Rab5-driven early endosome enlargement, defective retrograde axonal transport, accumulation of ubiquitinated protein aggregates, and impaired autophagy—all hallmarks of a dying-back motor neuron pathology.

Alternate Names for ALS2

ALS2; amyotrophic lateral sclerosis 2 (juvenile); ALS2CR6, amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 6; alsin; amyotrophic lateral sclerosis 2 protein; amyotrophic lateral sclerosis 2 chromosomal region candidate gene 6 protein; ALSJ; PLSJ; IAHSP; ALS2CR6

• 1. Yang Y, et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001 Oct;29(2):160-5.
  2. Miceli M, et al. ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules. Biology (Basel). 2022 Jan 5;11(1):77.