Research

The autophagy-lysosomal pathway is a key homeostatic process whereby damaged cytoplasmic components, misfolded proteins, and dysfunctional organelles are sequestered within autophagosomes for lysosomal degradation. In neurons, autophagosomes are robustly generated in axons and synaptic terminals. Nascent autophagosomes undergo long-distance retrograde transport toward the soma for cargo clearance within lysosomes. Given the post-mitotic nature of neurons, autophagy dysfunction is detrimental to neurons and has been implicated in aging and many neurodegenerative disorders, including Alzheimer’s disease (AD).

Autophagy-lysosomal pathway in normal and AD neurons

Mitochondria are essential for neuronal function and survival. Damaged mitochondria not only produce energy less efficiently but also release harmful reactive oxygen species (ROS) and initiate apoptotic signaling cascades, which have been linked to major neurodegenerative diseases, including AD and Parkinson’s disease (PD). Mitophagy, a cargo-selective autophagy for the elimination of defective mitochondria, plays a central role in mitochondrial quality control in neurons.

Mitophagy in normal and AD neurons

                                    GFP-Rheb                                                                                                                                                      DsRed-Mito

                                                                                                                                                                                               ← Retrograde

The focus of our research is to elucidate cellular mechanisms regulating autophagy-lysosomal function and mitochondrial quality and their impacts on axonal homeostasis and neurodegeneration. We are particularly interested in addressing the following questions: (1) how autophagy-lysosomal function is regulated in neurons and how deregulation in this key cellular clearance system triggers neurodegeneration and functional deficits, (2) how mitochondrial quality is controlled under physiological and pathophysiological conditions, (3) how inter-mitochondrial contact dynamics is regulated in healthy and diseased neurons, (4) Whether and how neuronal signaling is modulated by the endolysosomal system and whether defects in such a mechanism contribute to axonal degeneration, (5) how mitochondrial bioenergetics modulates cellular processes essential for the activity of glial cells. We apply a multidisciplinary approach to address these questions. Our goal is to shed light on fundamental knowledge of neurobiology and deepen our understanding of disease mechanisms that can provide a basis for the identification of novel protective and therapeutic opportunities to overcome AD and other neurodegenerative diseases.

Mitochondrial bioenergetics stimulates autophagy in tauopathy neurons