Position title: Professor, Biomolecular Chemistry
- Organ System/Disease Focus:
- Neurodegenerative disease (Hereditary spastic paraplegia) and cancer
- Aligned Research Focus:
- Basic stem cell science
We previously identified and characterized the impact of a point mutation observed in two adolescent patients who exhibit a complicated form of hereditary spastic paraplegia (HSP), which alters a highly conserved residue within Trk-fused gene (TFG). Wasting of hand and leg muscles, as well as electromyography findings, indicated additional neuropathy, whereas there was limited evidence for sensory involvement. Importantly, our previously published findings indicated that TFG functions on subdomains of the endoplasmic reticulum (ER) to regulate anterograde vesicle transport, which is mediated by COPII-coated carriers. Although COPII function has been implicated directly in dendritic growth, its potential role in axonal development and maintenance remains less clear. The single amino acid change in TFG (p.R106C) that causes HSP impairs the ability of TFG to oligomerize normally, which adversely affects its function in vivo. Our goal is to generate a human induced pluripotent stem cell (hiPSC) model for HSP. We are using genome engineering techniques to create hiPSCs that express TFG (p.R106C), which will be differentiated into cortical (telencephalic) glutamatergic neurons in culture for analysis. Using this system, we will determine the impact of mutations in TFG that cause neurodegenerative disease.
Shankar, R., Lettman, M.M., Whisler, W., Frankel, E.B., and Audhya, A. (2022) The ESCRT machinery directs quality control over inner nuclear membrane architecture. Cell Rep. 38:110263
Quinney, K., Frankel, E.B., Shankar, R., Kasberg, W., Luong, P., and Audhya, A. (2019) Growth factor stimulation promotes multivesicular endosome biogenesis by prolonging recruitment of the late-acting ESCRT machinery. Proc. Natl. Acad. Sci. USA. 116: 6858-686.
Slosarek, E.L.#, Schuh, A.L.#, Pustova, I.#, Johnson, A., Bird, J., Johnson, M., Frankel, E.B., Bhattacharya, N., Hanna, M.G., Burke, J.E., Ruhl, D.A., Quinney, K., Block, S., Peotter, J.L., Chapman, E.R., Sheets, M.D., Butcher, S.E., Stagg, S.M., and Audhya, A. (2018) Pathogenic TFG mutations underlying hereditary spastic paraplegia impair secretory protein trafficking and axon fasciculation. Cell Rep. 24: 2248-2260. (# denotes equal contribution)
Frankel, E.B., Shankar, R., Moresco, J.J., Yates, J.R., Volkmann, N., and Audhya, A. (2017) Ist1 regulates ESCRT-III assembly and function during multivesicular endosome biogenesis in Caenorhabditis elegans embryos. Nat. Commun. 8: 1439.
Hanna, M.G., Block, S., Frankel, E.B., Hou, F., Johnson, A., Yuan, L., Knight, G., Moresco, J.J., Yates, J.R., Ashton, R., Schekman, R., Tong, Y., and Audhya, A. (2017) TFG facilitates outer coat disassembly on COPII transport carriers to promote tethering and fusion with ER-Golgi intermediate compartments. Proc. Natl. Acad. Sci. USA. 114: E7707-E7716.
- Wang, L., Johnson, A., Hanna, M., and Audhya, A. (2016) Eps15 membrane binding and bending activity acts redundantly with Fcho1 during clathrin-mediated endocytosis. Mol. Biol. Cell. 27: 2676-2687. (Cover)