The autophagy-lysosomal pathway is essential for neuronal homeostasis. Defects within this pathway have been directly linked to a growing number of neurodevelopmental and neurodegenerative disorders. Retrograde transport of late endocytic organelles to the cell body is required for maintaining efficient degradation capacities in the autophagy-lysosomal system. Autophagy is also a critical regulator of organelle homeostasis, particular of mitochondria. The focus of my research is to elucidate the molecular and cellular mechanisms regulating the autophagy-lysosomal system and its impact on neuronal homeostasis and axonal degeneration. We are particularly interested in addressing the following questions: (1) How does retrograde transport of late endocytic organelles impact on autophagy-lysosomal function? (2) What is the mechanism regulating late endosome-lysosomal trafficking? (3) How is the mitochondrial quality controlled through mitophagy? (4) What are the mechanisms regulating neuronal morphology and synapse formation via the autophagy-lysosomal system? (5) How do defects within this system contribute to neurodegeneration?
Defective autophagy-lysosomal degradation and accumulation of damaged mitochondria and aggregated proteins have been implicated in the pathogenesis of major neurodegenerative diseases. Our long-term goal is to identify the cellular mechanisms for proper turnover of dysfunctional mitochondria through mitophagy and clearance of protein aggregates by enhancing autophagy-lysosomal function. We will evaluate if up-regulation of this system ameliorates neuropathology, restores cognitive function, and attenuates behavioral abnormalities associated with a variety of neurodegenerative diseases. These advances in our understanding of the regulatory mechanisms of autophagy-lysosomal function will provide a basis for the development of novel protective therapies to overcome major neurodevelopmental and neurodegenerative disorders.