Understanding Neuronal Autophagic Lysosomal Pathways Through Genetic and Pharmacological Perturbations

The autophagy lysosomal system is necessary for protein turnover, especially in long-lived neurons that have complex morphology. The adaptor protein JIP3 is critical for this process. However, despite its importance to axonal lysosome retrograde transport, the role of JIP3 in axonal transport of less mature autolysosomes and autophagosomes in mammalian neurons has not yet been described. Additionally, the impact of disrupting axonal lysosomal transport on neuronal autophagy has not yet been fully elucidated. In this thesis, we address both questions and, in the process, further contextualize the role of JIP3 in overall neuronal function. We found that JIP3 is critical for preventing accumulation of autophagic vacuoles during retrograde axonal transport and that loss of JIP3 is associated with decreased mitochondrial and synaptic proteins in axons. Further, our results suggest that JIP3 has functions in the endolysosomal system in the soma. Finally, we observed that mitigating JIP3 pathology by increasing autophagic flux can rescue transport deficits and elevated Aβ species. These findings provide pathophysiologic insight into various disease processes, including disorders of intellectual development and developmental delay as well as neurodegeneration.

Author dc:creator

• Amanda Snead (24400178)

• Biology, Neuroscience
• Biology, Cell

Statement dc:rights

• In Copyright
• Open Access after 2028-05-01

DOI dc:identifier

https://doi.org/10.25417/uic.32995232.v1

OAI identifier oai:identifier

oai:figshare.com:article/32995232