Characterization of Alsin and Its Role in IGF-1-Mediated Neuronal Survival

The transport of proteins between organelles is a highly regulated and complex process that is crucial for many of the functions required for cellular homeostasis. Many distinct proteins are involved in each trafficking step with roles in vesicle formation, budding, movement, and fusion. One class of proteins, the Rab GTPases, is required for docking and fusion of transport vesicles with their target membrane. These proteins are regulated by their state of nucleotide binding, with GTP-bound Rabs thought to provide specificity to transport steps via their interactions with specific effector proteins.
While much work has been focused on proteins downstream of Rab GTPases, little is known as to how the activation of these proteins is controlled. This is particularly true of Rab5, the Rab protein required for vesicle fusion at the endosome. Endocytosis of plasma membrane proteins requires Rab5(GTP, and humans possess at least seven proteins (Vps9 family) that are expected to activate Rab5. An intriguing aspect of the Vps9 family of proteins is that they appear to link signal transduction to receptor trafficking via the specific coupling of particular receptors to Rab5-mediated endocytosis.
Cell biological, biochemical, and immunohistochemical techniques were employed to characterize one of the Vps9 family proteins named Alsin. Alsin is required for motor neuron maintenance and/or survival, as loss-of-Alsin function results in multiple juvenile-onset neurodegenerative disorders (ALS2, JPLS, IAHSP). It was found here that Alsin is an endosomal protein that activates both Rac1 and Rab5. This protein is present in all of the tissues associated with the aforementioned diseases and intriguingly is upregulated in the cerebellum, an unknown site of pathology for this class of disorders. Alsin was found to couple Rab5 activation specifically to the IGF-1 signal transduction pathway via its regulation of IGF-1 receptor endocytosis. This function of Alsin was shown to be essential for IGF-1-mediated cell survival. These results provide the first characterization of Alsin and identify a novel cause for neurodegeneration.