Autophagy is a key homeostatic process whereby autophagosomes engulf damaged cytoplasmic components, misfolded proteins, and dysfunctional organelles for lysosomal degradation. In neurons, autophagosomes are predominantly generated in axons and at synaptic terminals and undergo robust retrograde axonal transport toward the soma where mature lysosomes are mainly located. The autophagy-lysosomal pathway is essential for the maintenance of neuronal homeostasis, and defects within this pathway have been implicated in a variety of neurological disorders.
Mitochondria are essential for neuronal function and survival. Damaged mitochondria not only produce energy with less efficiency, but also release harmful reactive oxygen species (ROS) and initiate apoptotic signaling cascades, which have been linked to the pathogenesis of major neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Mitophagy, a selective autophagy for the removal of defective mitochondria, is a key cellular pathway for mitochondrial quality control in neurons.
The focus of our research is to elucidate cellular mechanisms regulating axonal transport, membrane trafficking, and autophagy-lysosomal function and theirs impact on axonal homeostasis and neurodegeneration. We are particularly interested in addressing the following questions: (1) How is autophagy-lysosomal function regulated in neurons? (2) How is mitochondrial quality controlled in neurons under physiological and pathophysiological conditions? (3) Is mitochondrial quality control involved in the regulation of mitochondrial energetic status and thus energy metabolism in neurons? (4) Is neuronal signaling modulated by endolysosomal system? (5) How do defects in these mechanisms contribute to axonal degeneration? (6) What are the mechanisms regulating neuronal morphogenesis and synapse formation through the autophagy-lysosomal pathway?
Our studies have provided the evidence of dynamic and spatial mitophagy in eliminating damaged mitochondria in live mature neurons. We reveal that impaired axonal transport and inadequate mitophagy capacity contribute to autophagic stress and mitochondrial deficits in AD neurons. Our long-term goal is to identify molecular modifiers for efficient clearance of aged and damaged mitochondria and protein aggregates associated with aging and neurodegenerative diseases. We will evaluate whether enhanced autophagy-lysosomal function ameliorates neuropathology and attenuates behavioral abnormalities linked to major neurodegenerative diseases. The advance in our understanding of these mechanisms will provide a basis that could lead to the development of novel protective and therapeutic approaches to overcome these neurological disorders.
