| Autophagy, a lysosome-dependent degradation mechanism, mediates many biological processes including cellular stress responses and neuroprotection. Here, I demonstrate that autophagy positively regulates development of the Drosophila larval neuromuscular junction (NMJ). Autophagy induces an NMJ overgrowth phenotype closely resembling that of highwire (hiw), an E3 ubiquitin ligase mutant. Moreover, like hiw, autophagy-induced NMJ overgrowth is suppressed by wallenda (wnd) and by a dominant-negative JNK (bsk DN). I show that autophagy promotes NMJ growth by reducing Hiw levels. Thus autophagy and the ubiquitin proteasome system converge in regulating synaptic development. Because autophagy is triggered in response to many environmental cues, those findings suggest that it is perfectly positioned to link environmental conditions with synaptic growth and plasticity.;In the second project, I characterized a critical neuroprotective role of dNSF1 in Drosophila. Mutations in dNSF1 result in neurodegeneration and early death. These studies indicate that these phenotypes are not secondary consequences of defects in dNSF1's well-characterized role in synaptic transmission. Instead, they reveal that dNSF1 performs an additional neuroprotective role, further supported by the finding that overexpression of dNSF1 + prevented alpha-Synuclein induced loss of dopaminergic neurons. The increase in the accumulation of high molecular weight ubiquitinated protein in comt brains at restrictive temperature together with a decrease in lysosomes has led us to hypothesize that comt is defective in autophagy, a known neuroprotective pathway. |
