Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare, early-onset autosomal recessive motor neuron disease associated with mutations in ALS2.
Recessive mutations in the alsin gene cause three clinically distinct motor neuron diseases: juvenile amyotrophic lateral sclerosis (ALS2), juvenile primary lateral sclerosis (JPLS) and infantile-onset ascending hereditary spastic paraplegia (IAHSP).
Recently, it has been shown that ALS2 plays a role in neuroprotection against MND-associated pathological insults, such as toxicity induced by mutant Cu/Zn superoxide dismutase (SOD1).
To our knowledge, these data provide the first example of non-cell-autonomous glial effects in a recessive form of motor neuron disease and a potential rationale for the higher vulnerability of upper versus lower motor neurons in ALS2/Alsin-linked disorders.
To test whether ALS2 plays a protective role against mutant SOD1-mediated motor neuron degeneration in vivo, we examined the progression of motor neuron disease in SOD1(G93A) mice on an ALS2 null background.
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.
Recessive mutations in ALS2 (juvenile amyotrophic lateral sclerosis) are causative for early-onset upper motor neuron diseases, including infantile ascending hereditary spastic paralysis (IAHSP).
Homozygous mutation in the ALS2 gene and the resulting loss of the guanine exchange factor activity of the ALS2 protein is causative for autosomal recessive early-onset motor neuron disease that is thought to predominantly affect upper motor neurons.
Mutation of the ALS2 gene encoding alsin is linked to the onset of autosomal recessive motor neuron diseases, including juvenile-onset amyotrophic lateral sclerosis (ALS).
Thus, mutations in the ALS2 gene linked to early-onset motor neuron disease uniformly produce loss of activity through decreased protein stability of this endosomal GEF.
Eight mutations in the ALS2 gene have been described as causing autosomal-recessive juvenile-onset forms of the motor neuron diseases amyotrophic lateral sclerosis, primary lateral sclerosis and hereditary spastic paraplegia.
Thus, mutations in the ALS2 gene linked to early-onset motor neuron disease uniformly produce loss of activity through decreased protein stability of this endosomal GEF.