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Colloquium CO7: Mechanisms of Endocyclic Trafficking in Health and Neurodegenerative Disease

Rab5 is the small GTPase responsible for directing the targeting of receptor-bearing endocytic vesicles that have budded from the plasma membrane to early endosomes. Activating Rab5 is a critical regulation point in this trafficking event, and Rab5 activation is carried out by guanine nucleotide exchange factors (GEFs) containing Vps9 domains. More than 10 Vps9 domain-containing proteins have been identified in eukaryotes, including the ALS2 gene product Alsin. ALS2 is mutated in a recessive juvenile-onset form of ALS and has also been linked to juvenile primary lateral sclerosis (JPLS) as well as infantile-onset ascending hereditary spastic paraplegia (IAHSP). We, and others, have previously shown that Alsin is a Rab5 and Rac1 GEF. In an effort to understand the molecular basis of juvenile ALS, we have chosen to examine the functional role of Alsin in neuron maintenance using a cell culture model system. We have found that insulin-like growth factor 1 (IGF-1) signaling is significantly impaired in cells expressing mutant Alsin lacking an intact Rab5 GEF domain. Though IGF-1 receptor activation and internalization were unaffected, trafficking of activated receptors to early endosomes was severely compromised. Since IGF-1 plays an important role in mediating cell survival, we examined IGF-1 anti-apoptotic activity in cells expressing the mutant form of Alsin. The IGF-1 signaling defect observed in Alsin defective cells also resulted in reduced IGF-1 protection from serum withdrawal-induced apoptosis. We conclude that Alsin is required for IGF-1 receptor traffic, IGF-1 signaling, and IGF-1 mediated cell survival, identifying a potential mechanism for motor neuron degeneration observed in juvenile-onset ALS.