Mitochondria supply ATP essential for neuronal growth and function. Neurons face an exceptional challenge to maintain energy homeostasis in distal axons, synapses, and growth cones. Anchored mitochondria serve as local energy sources; thus, regulation of mitochondrial trafficking and anchoring in axons and synapses ensures that metabolically active areas are adequately supplied with ATP. In addition, anchored mitochondria need to be removed as they age or become dysfunctional. Mitochondrial dysfunction and impaired transport are hallmark features of several major neurodegenerative diseases. Investigations into the regulation of mitochondrial trafficking and anchoring represent an important emerging area. Our central hypothesis is that mitochondrial trafficking and distribution is tightly regulated in order to sense, integrate, and respond to changes in metabolic and growth status, synaptic activity, aging, and pathological stress. Our ongoing investigations are focused on addressing five fundamental questions: (1) how axonal mitochondria are recruited to and captured at active presynaptic terminals); (2) how mitochondria anchoring mechanisms are turned on or off by sensing of local ATP levels; (3) how energy signaling pathways enable neurons to distribute axonal mitochondria into areas where energy consumption is high during development, regeneration, and adult neurogenesis; (4) how neurons maintain and recover stressed mitochondria prior to the activation of Parkin-mediated mitophagy under physiological and pathological conditions; and (5) how oligodendrocyte-neuron interplay maintains axonal energy homeostasis by enhancing local mitochondrial energetics.

Lysosomes serve as degradation hubs for autophagic and endocytic components, thus maintaining degradation capacity and cellular homeostasis essential for neuronal survival and function. Endo-lysosomal trafficking delivers targeted materials to mature lysosomes for degradation. The majority of autophagic and endocytic organelles undergo long-distance retrograde transport from distal axons toward the soma, where mature lysosomes are highly enriched. To achieve effective degradation capacity in distal regions, active lysosomes are also recruited to axons under physiological and pathological conditions. Therefore, regulation of bi-directional transport of these organelles plays a critical role in the maintenance of axonal and synaptic homeostasis. Autophagy-lysosomal dysfunction contributes to the pathogenesis of several neurodegenerative diseases and axonal dystrophy of lysosomal storage disorders (LSDs). However, mechanistic contributions of impaired endo-lysosome trafficking and lysosomal dysfunction to disease onset and progression remain elusive. Our research program is aimed at addressing the following fundamental issues: (1) how neurons recruit active lysosomes into distal axons to effectively eliminate protein aggregates and damaged organelles; (2) how chronic lysosomal dysfunction in LSDs compromises axonal delivery of lysosomes, thus leading to axonal dystrophy; (3) how impaired autophagic transport in dopaminergic neurons (DAs) contributes to PD-linked autophagy-lysosome dysfunction, axon degeneration, and DA neuron death; and (4) how aging-associated oxidation stress impairs autophagy-lysosomal distribution and function in distal axons.

The formation of new synapses and maintenance and remodeling of mature synapses require targeted delivery of newly synthesized presynaptic cargoes from the soma to synapses. We previously identified syntabulin as a kinesin-1 motor adaptor that mediates axonal transport of presynaptic cargos to synapses. Knockdown of syntabulin reduces axonal delivery of presynaptic components and impairs synaptic formation and activity-dependent synaptic remodeling. A recent genetic study of autism patients identified a de-novo syntabulin variant that abolishes its interaction with KIF5. Thus, there is an urgent need to establish axonal transport and presynaptic mechanisms underlying autism-associated phenotypes. Using syntabulin cKO mice and an autism-linked syntabulin de-novo mutation, we investigate whether defective presynaptic cargo transport serves as a new presynaptic mechanism contributing to the pathogenesis of autism.

These specific aims are closely interrelated, as mitochondrial transport, mitophagy, energy homeostasis, autophagy and lysosomal function, and presynaptic maintenance are highly coordinated and mechanistically linked. We have applied cutting edge live imaging assays in a multidisciplinary systems analysis of genetic mice combined with gene rescue experiments. Our syntaphilin, snapin and syntabulin mice display striking phenotypes in axonal transport of mitochondria, endosomes, and presynaptic cargos. Pursuing these studies will advance our knowledge of fundamental processes affecting neurodevelopmental and neurodegenerative disorders, regeneration, and neurogenesis.