Neuronal Autophagy
The goal of our research program is to determine the mechanisms and regulation of autophagy in neuronal homeostasis and how defects in autophagy contribute to neurodegenerative disease. We are defining the autophagy pathway in primary neurons. Our research established a new paradigm for the mechanisms of autophagy in neurons, a paradigm distinct from observations in yeast and smaller, less-polarized mammalian cells. We established that autophagy in the axon of primary neurons is a vectorial process that delivers cargo from the distal axon to the soma. Autophagosomes are preferentially generated in the distal axon and undergo robust retrograde transport to the soma for effective cargo degradation (Maday et al., J. Cell Biol., 2012; Maday and Holzbaur, Dev. Cell, 2014). Surprisingly, canonical autophagy inducers that activate autophagy in non-neuronal cells, do not effectively upregulate autophagy in neurons, suggesting neuron-specific mechanisms of autophagic regulation (Maday and Holzbaur, J. Neurosci., 2016). Thus, our research has revealed that while the fundamental core machinery required for autophagosome formation in neurons is conserved from yeast and smaller less-polarized mammalian cells, the spatiotemporal regulation of autophagy in neurons is distinct from these model systems. Our research is focused around 3 major themes:
Spatiotemporal mechanisms of autophagosome biogenesis, maturation, and cargo degradation in neurons
What is the molecular basis for autophagy in dendrites, the axon, and the soma? How are autophagosomes generated and how do they mature into degradative organelles to eliminate cargo within the neuron? How is this achieved within each compartment of the neuron?
The contribution of autophagy to neural function
What is the interplay between autophagy and neuronal activity? How is autophagy regulated in pre- and post-synaptic domains to impact neural activity? How is autophagy important for maintaining neural function of the developing and mature brain?
The role of autophagy in neuronal stress and disease
How is neuronal autophagy regulated in response to various modalities of stress such as metabolic, excitotoxic, and proteotoxic stress? How do alterations in autophagy contribute to neurodegeneration and how can autophagy be modulated for therapeutic purposes?
