Disease relevance of Als2

• However, immunohistochemical and electrophysiological analyses identified an age-dependent, slowly progressive loss of cerebellar Purkinje cells and disturbance of spinal motor neurons associated with astrocytosis and microglial cell activation, indicating a subclinical dysfunction of motor system in Als2-null mice [1].
• ALS2 is an autosomal recessive form of spastic paraparesis (motor neuron disease) with juvenile onset and slow progression caused by loss of function of alsin, an activator of Rac1 and Rab5 small GTPases [2].
• OBJECTIVE: Recessive mutations in alsin, a guanine-nucleotide exchange factor for the GTPases Rab5 and Rac1, cause juvenile amyotrophic lateral sclerosis (ALS2) and related motoneuron disorders [3].

High impact information on Als2

• There is a significant decrease in the size of cortical motor neurons, and Als2(-/-) mice are mildly hypoactive [2].
• Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities [2].
• ALS2/alsin is a member of guanine nucleotide exchange factors for the small GTPase Rab5 (Rab5GEFs), which act as modulators in endocytic pathway [1].
• Alsin knockdown induced cell death in 32 to 48% of motoneurons and significantly inhibited axon growth in the surviving neurons [3].
• Immunofluorescence and fractionation experiments in both fibroblasts and neurons revealed that alsin is a cytosolic protein, with a significant portion associated with small, punctate membrane structures [4].

Biological context of Als2

• Collectively, while loss of ALS2 does not produce a severe disease phenotype in mice, these Als2-null animals should provide a useful model with which to understand the interplay between endosomal dynamics and the long-term viability of large neurons such as Purkinje cells and spinal motor neurons [1].
• ALS2 encodes a large protein termed alsin, which contains a number of predicted cell signaling and protein trafficking sequence motifs [4].
• Our transfection experiments in cultured cells suggest that Alsin is a cytoskeletal protein with dual endosomal and centrosomal localizations [5].

Anatomical context of Als2

• We also found that alsin was present in membrane ruffles and lamellipodia [4].
• These data suggest that alsin is involved in membrane transport events, potentially linking endocytic processes and actin cytoskeleton remodeling [4].
• Alsin is partially associated with centrosome in human cells [6].
• Here we used the tetracycline-regulated expression system to overexpress the full-length and truncated forms of Alsin in different cell lines [6].

Analytical, diagnostic and therapeutic context of Als2

• To establish an animal model of ALS2 and derive insights into the pathogenesis of this illness, we have generated alsin-null mice [2].
• METHODS: To generate an alsin loss-of-function model in an ALS-relevant cell type, we developed a new small interfering RNA electroporation technique that allows efficient knock down of alsin in embryonic rat spinal motoneurons [3].

References