Research Projects

Synaptopathies are a group of neurodegenerative disorders, encompassing, but not limited to, Alzheimer’s and Parkinson’s diseases and are often characterized by dysfunctional synapses. Neuronal synapses are highly dynamic structures and thus, particularly susceptible to accumulating damaged proteins. Dysfunctional synapses may result in compromised neuronal networks and brain damage. Thus, the proteostatic machinery in neurons is highly controlled to meet specific requirements, which, when unmet, contribute to protein aggregate accumulation, resulting in a plethora of diseases including neurodegeneration. This proposal is on the premise that relative impairment of the proteostasis machinery with respect to efficient maintenance of cellular homeostasis may be sufficient in driving disease pathogenesis. In addition, restoring the proteostasis balance may rescue this phenotype. Autophagy is one of the proteostatic machineries wherein, a part of the cytoplasm is sequestered in double membraned vesicles called autophagosomes that eventually fuse with lysosomes resulting in degradation of its contents. Autophagy in neurons, unlike in other cells, is highly compartmentalized. In each compartment such as the soma, dendrites, axon and pre-synapse, autophagosome biogenesis and degradation takes place locally and is differentially regulated. Among these, surprisingly, autophagosome biogenesis majorly occurs not in the soma, but rather in the pre-synapse. Emerging studies suggest that proteostatic machineries, especially synaptic autophagy can confer neuroprotection by clearing toxic protein aggregates at the pre-synapse. Therefore, key to understanding modulation of pre-synaptic autophagy would be to identify and characterize synapse-specific autophagy regulators. We also hypothesize that such regulators while playing critical roles in maintaining presynaptic autophagy, will also serve as a druggable target for synaptopathies. Our study design involves in silico approaches to identify potential regulators (having human homologues) of autophagosome biogenesis in the pre-synapse. Drosophila melanogaster neuromuscular junctions provide an ideal platform for in vivo testing of the hits obtained from bioinformatic analysis. Thus, these hits will be investigated in a genetic screen using Drosophila melanogaster for their potential to modulate presynaptic autophagy. Detailed characterization of the identified regulators will then be carried out in human and mouse neuronal cultures. Finally, we will use genetic (loss-of-function) and pharmacological (small molecule modulators of autophagy) approaches to validate the ability of these genes to regulate autophagy flux in presence and absence of protein aggreagtes such as alpha-synuclein and Abeta. Thus, this work should not only identify genetic risk factors and causes for neurodegenerative disorders associated with synaptopathies but also provide potential therapeutic targets for prophylaxis.