Anjon Audhya

Anjon Audhya
Title
Associate Professor Department of Biomolecular Chemistry
Phone
608-262-3761
E-mail
audhya@wisc.edu

Education:

Ph.D. University of California- San Diego

Lab Website:

http://www.audhyalab.org/

Research Focus:

Organelle dynamics and neuronal trafficking; Neuronal control of motor function

Research Strength: 

Neurobiology of Disease; Perception and Movement

Research Description:

Synaptic transmission depends on the constant microtubule-based transport of organelles and vesicles to and from the distal portions of axons and dendrites. Defects in these processes can lead to a variety of neurodegenerative disorders. In particular, hereditary spastic paraplegias (HSPs) arise from a length-dependent axonopathy of corticospinal motor neurons. This diverse group of disorders is characterized by progressive lower-limb spasticity and weakness and has been linked to more than 70 unique genetic loci, many of which encode proteins that function in cytoskeleton and organelle homeostasis. However, mechanistic insights into the direct effect of mutations that cause HSPs are lacking.

In collaboration with a number of groups from around the world, we have identified and characterized the impact of point mutations observed in children who exhibit a complicated form of HSP, which alters highly conserved residues within Trk-fused gene (TFG). 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 changes in TFG (p.R22W and p.R106C) that cause HSP impairs the ability of TFG to oligomerize normally, which adversely affects its function in vivo. In non-neuronal cells, our initial studies demonstrate that inhibition of TFG results in the collapse of the ER network onto the underlying microtubule cytoskeleton, dramatically altering its morphology and dynamics. Furthermore, the distribution of mitochondria within cells lacking TFG function is highly abnormal, suggesting that TFG may function to coordinate interactions between multiple organelles and microtubules. Our goal is to explore this idea and define new mechanisms that sustain and enhance neuron viability and activity during development and aging. Recently, using CRISPR-mediated genome editing, we have developed rodent models of HSP. Our goal is to take advantage of these animals, together with models developed using human stem cells, and define the mechanistic basis of HSPs.

Selected Publications:

Hanna, M.G., Mela, I., Wang, L., Henderson, R.M., Chapman, E.R., Edwardson, J.M., and Audhya, A. (2016) Sar1 GTPase activity is regulated by membrane curvature. J. Biol. Chem. 291: 1014-1027.

Callaci, S., Morrison, K., Shao, X., Schuh, A.L., Wang, Y., Yates, J.R. 3rd, Hardin, J., and Audhya, A. (2015) Phosphoregulation of the C. elegans cadherin-catenin complex. Biochem. J. 472:  339-352.

Johnson, A., Bhattacharya, N., Hanna, M., Pennington, J.G., Schuh, A.L., Wang, L., Otegui, M.S., Stagg, S.M., and Audhya, A. (2015) TFG clusters COPII-coated transport carriers and promotes early secretory pathway organization. EMBO J. 34:  811-827.

Schuh, A.L., Hanna, M., Quinney, K., Wang, L., Sarkeshik, A., Yates, J.R., and Audhya, A. (2015) The VPS-20 Subunit of the Endosomal Sorting Complex ESCRT-III Exhibits an Open Conformation in the Absence of Upstream Activation. Biochem. J. 466:  625-637.

Takahashi, H., Mayers, J.R., Wang, L., Edwardson, J.M., and Audhya, A. (2015) Hrs and STAM function synergistically to bind ubiquitin-modified cargoes in vitro. Biophys. J. 108:  76-84.

Shen, Q., Schuh, A.L. Zheng, Y., Quinney, K., Wang, L., Hanna, M., Mitchell, J.C., Otegui, M.S., Ahlquist, P., Cui, Q., and Audhya, A. (2014) Mechanisms governing ESCRT-III spiral filament assembly. J. Cell Biol. 206:  763-777.

Mayers, J.R., Wang, L., Pramanik, J., Johnson, A., Sarkeshik, A., Wang, Y., Saengsawang, W., Yates, J.R., and Audhya, A. (2013) Regulation of ubiquitin-dependent cargo sorting by multiple plasma membrane endocytic adaptor proteins. Proc. Natl. Acad. Sci. USA. 110:  11857-11862.

Beetz, C., Johnson, A., Schuh, A., Thakur, S., Varga, R., Fothergill, T., Hertel, N., Bomba-Warczak, E., Thiele, H., Nurnberg, G., Altmuller, J., Saxena, R., Chapman, E.R., Dent, E.W., Nurnberg, P., and Audhya, A. (2013) Inhibition of TFG function causes hereditary axon degeneration by impairing ER structure. Proc. Natl. Acad. Sci. USA. 110:  5091-5096.