Dr. Jon Audhya

Membrane Trafficking Program at the University of Wisconsin-Madison

Title: Organelle Homeostasis in Development and Disease.

Abstract
Mutations in Trk-fused gene (TFG) have been linked to numerous forms of neurodegenerative disease. Using a combination of single particle electron microscopy approaches, small angle x-ray scattering, x-ray crystallography, and human stem cell models, we have determined the direct impacts of several of these mutations. In particular, mutations within the TFG amino-terminus alter the conformation of TFG ring complexes, which play an important role in the kinetics of secretory protein export from the endoplasmic reticulum (ER). Consistent with this idea, we find that cells harboring TFG mutations exhibit constitutively elevated levels of ER stress. Moreover, we find that neurons expressing these mutants fail to display normal axon bundling, suggesting that a deficit in protein export from the ER plays an important role during neurite outgrowth.

Figure: Early secretory pathway organization resolved using electron tomography