Autophagy in neurodegeneration and inflammation and novel modulators of macroautophagy

Deregulated autophagy leads to protein accumulation and has been linked to aging, inflammation and neurodegenerative disease. While studying cell aging we found an expression switch between co-chaperones BAG1 and BAG3 during aging and acute stress triggering BAG3-mediated autophagic degradation of aggregated proteins (e.g. mtSOD1) in vitro and in vivo. BAG3-mediated selective macroautophagy is an important adaptation of the PQC to pro-oxidant and aggregation-prone conditions. Recently, we performed a RNAi screen in C.elegans and identified rbg-1 as modifier of protein aggregation and autophagy. The mammalian ortholog RAB3GAP1/2, components of the TBC domain-free RAB3GAP complex, affect autophagy at basal and rapamycin-induced conditions also in human fibroblasts. RAB GTPase activating proteins (RABGAPs) are important factors for vesicle transport. Correlating the activity of RAB3GAP1/2 with ATG3 and ATG16L1 and analyzing ATG5 punctate structures, we found that the RAB3GAPs actually modulate autophagosomal biogenesis: RAB3GAP1/2 colocalizes with lipid droplets, and their autophagy modulatory activity depends on GTPase activating activity of RAB3GAP1.