Autophagy is a key homeostatic process whereby autophagosomes engulf damaged cytoplasmic components, protein aggregates, and dysfunctional organelles for lysosomal degradation. In neurons, autophagosomes are predominantly formed in distal axons and presynaptic terminals and undergo exclusively retrograde transport toward the soma where mature lysosomes are mainly located. The autophagy-lysosomal pathway is essential for the maintenance of neuronal homeostasis. Defects in this pathway have been implicated in a growing number of neurological disorders.
Mitochondria are essential organelles for neuronal function and survival. Dysfunctional mitochondria not only produce energy less efficiently, but also release harmful reactive oxygen species and initiate apoptotic signaling cascades, which have been linked to the pathogenesis of major neurodegenerative diseases including Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis, and Huntington’s. Efficient elimination of aged and damaged mitochondria through mitophagy is a key cellular pathway for mitochondrial quality control in neurons.
The focus of our research is to elucidate the molecular and cellular mechanisms regulating the autophagy-lysosomal system and their impact on neuronal homeostasis in health and axonal degeneration. We are particularly interested in addressing the following questions: (1) What are the mechanisms regulating axonal transport, membrane trafficking, and autophagy-lysosomal function? (2) How is mitochondrial quality controlled through mitophagy in heathy and diseased neurons? (3) How is the endolysosomal system involved in the regulation of neuronal signaling? (4) How do defects in these mechanisms contribute to neurodegeneration? (5) What are the mechanisms regulating neuronal morphogenesis and synapse formation through the autophagy-lysosomal pathway?
Our study provides the evidence of dynamic and spatial Parkin-mediated mitophagy in elimination of defective mitochondria in live neurons. We reveal that inadequate mitophagy capacity contributes to mitochondrial defects in Alzheimer’s disease neurons. Our long-term goal is to elucidate the cellular mechanisms for proper turnover of damaged mitochondria and clearance of protein aggregates by enhancing autophagy-lysosomal function. We will evaluate if up-regulation of this system ameliorates neuropathology and attenuates behavioral abnormalities associated with major neurodegenerative diseases. The advance in our understanding of these mechanisms will provide a strong basis that could lead to the development of novel protective and therapeutic approaches.
Induction of Parkin-mediated mitophagy in neurons
Mitophagy induction in Alzheimer’s disease neurons
Autophagic stress at presynaptic terminals of Alzheimer’s disease neurons
Mechanisms underlying autophagic stress in Alzheimer’s disease neurons