Molecular Pathology of Lou Gehrig's Disease (ALS), a Fly's View

The goal of my laboratory is to uncover the molecular mechanisms underlying Amyotrophic Lateral Sclerosis (ALS). We will accomplish this by identifying core pathological defects caused by molecules implicated in familial ALS. We are currently focusing our work on VapB (Vamp associated protein B), in which a missense (P56S) mutation causes a familial form of ALS, ALS8. It is well established that dissecting pathways using animal models, including flies and mice, is a productive approach for the understanding of wild-type protein function and the effects of pathological mutations. Our data support the working model that impaired normal function of VAP causes a variety of cellular deficits, which lead to core pathological defects observed in familial and sporadic ALS. Significantly, our studies in flies have successfully uncovered several novel functions of Vap. We have found that VAP is required for regulation of Endoplasmic Reticulum (ER) stress (cell autonomous function). Vap is cleaved and secreted as a trophic factor (non-cell autonomous function). To determine if the ER stress and a failure of VAP secretion are relevant to ALS pathogenesis, we have been working on our newly created knock-in mice carrying the ALS8 mutation in vapb gene. Uncovering the functions and pathways in which Vap is operating will provide clues to develop strategies to delay the course of the disease.