Interdisciplinary Life Science - PULSe Great research is a matter of choice

Jean-Christophe (Chris) Rochet

Jean-Christophe (Chris)  Rochet Profile Picture

Associate Professor of Med Chem Mol Pharm
Ph.D. - 1998 - University of Alberta

Contact Info:

Training Group(s):
Biomolecular Structure and Biophysics
Chemical Biology
Integrative Neuroscience

Current Research Interests:

Research in my laboratory is aimed at understanding the role of protein aggregation in neurological and muscular disorders. Generally, proteins adopt a precise three-dimensional structure that determines their function. However, mutant polypeptides or proteins subjected to environmental stress are often incorrectly folded. At high concentrations, proteins that lack a compact fold tend to undergo spurious interactions to form abnormal, high-molecular-weight complexes. This phenomenon, referred to as protein "aggregation" or "misassembly," is associated with various human diseases. We have chosen to address the role of protein misassembly in three of these disorders: Parkinson's Disease (PD), amyotrophic lateral sclerosis (ALS), and desmin-related myopathy (DRM). Importantly, heritable forms of each disorder have been linked to the gene that encodes the characteristic misassembled protein associated with the disease. This observation is taken as evidence that protein aggregation plays a role in the pathogenesis of these diseases.

For all three diseases, we aim to answer the following questions:

(1) What are the molecular mechanisms (intermolecular interactions, conformational changes) underlying protein misassembly?

(2) How do post-translational modifications (e.g. oxidation, phosphorylation, ubiquitylation) affect protein aggregation?

(3) What are the cellular factors (e.g. chaperones, ubiquitin-conjugating enzymes, proteasome) that modulate protein misassembly?

(4) What are the molecular pathways (e.g. apoptosis, necrosis) by which protein aggregation causes disease?

These questions are addressed using an interdisciplinary approach, including biochemical and biophysical analyses of recombinant proteins and the development of yeast and mammalian cell models. Studies will also be carried out using transgenic Drosophila and C. elegans. The advantage of transgenic flies and worms as disease models is that they can be analyzed using reverse-genetic approaches to decipher molecular pathways underlying pathogenesis. Finally, an important goal is to identify small molecules via high-throughput screening to study and ultimately treat these devastating illnesses.

Selected Publications:

Hulleman, J.D., Mirzaei, H., Guigard, E., Taylor, K.L., Ray, S.S., Kay, C.M., Regnier, F.E., & Rochet, J.-C. 2007. Destabilization of DJ-1 by familial substitution and oxidative modifications: implications for Parkinson's disease. Biochemistry 46:5776-5789.

Outeiro, T.F., Kontopoulos, E., Altman, S., Kufareva, I., Strathearn, K.E., Amore, A.M., Volk, C.B., Maxwell, M.M., Rochet, J.-C., McLean, P.J., Young, A.B., Abagyan, R., Feany, M.B., Hyman, B.T., and Kazantsev, A. 2007. Sirtuin 2 inhibitors rescue alpha-synuclein toxicity in Parkinson's disease models. Science 317:516-519.

Zakharov, S.D., Hulleman, J.D., Dutseva, E.A., Antonenko, Y.N., Rochet, J.-C.*, & Cramer, W.A.* 2007. Helical alpha-synuclein forms ion channels. Biochemistry 46:14369-14379. *Co-corresponding authors.

Gitler, A. D., Bevis, B. J., Shorter, J., Strathearn, K. E., Hamamichi, S., Su, L. J., Caldwell, K. A., Caldwell, G. A., Rochet, J.-C., McCaffery, J. M., Barlowe, C., & Lindquist, S. 2008. The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc. Natl Acad. Sci. USA 105:145-150.

Liu, F., Nguyen, J. L., Hulleman, J. D., Li, L., & Rochet, J.-C. 2008. Mechanisms of DJ-1 neuroprotection in a cellular model of Parkinson's disease. J. Neurochem. 105:2435-2453.

Liu, F., Hindupur, J., Nguyen, J. L., Ruf, K. J., Zhu, J., Schieler, J. L., Bonham, C. C., Wood, K. V., Davisson, V. J., & Rochet, J.-C. 2008. Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's-related insults. Free Radic. Biol. Med., 45:242-255.

Pandey, A. P, Haque, F., Rochet, J.-C.*, & Hovis, J. S.* 2009. Clustering of alpha-synuclein on supported lipid bilayers: role of anionic lipid, protein, and divalent ion concentration. Biophys. J., 96:540-551. *Co-corresponding authors.

Gitler, A. D., Chesi, A., Geddie, M. L., Strathearn, K. E., Hamamichi, S., Hill, K. J., Caldwell, K. A., Caldwell, G. A., Cooper, A. A., Rochet, J.-C., & Lindquist, S. 2009. Alpha-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat. Genet., 41:308-315.

Su, L. J., Auluck, P. K., Outeiro, T. F., Yeger-Lotem, E., Kritzer, J. A., Tardiff, D. F., Strathearn, K. E., Liu, F., Cao, S., Hamamichi, S., Hill, K. J., Caldwell, K. A., Bell, G. W., Fraenkel, E., Cooper, A. A., Caldwell, G. A., McCaffery, J. M., Rochet, J.-C., & Lindquist, S. (2010) Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson disease models. Dis. Model. Mech., 3, 194-208.

Haque, F., Pandey, A. P., Cambrea, L. R., Rochet, J.-C.*, & Hovis, J. S.* (2010) Adsorption of a-synuclein on lipid bilayers: modulating the structure and stability of protein assemblies. J. Phys. Chem. B., 114, 4070–4081. *Co-corresponding authors.

Zheng, B., Liao, Z., Locascio, J. J., Lesniak, K. A., Roderick, S. S., Watt, M. L., Eklund, A. C., Zhang-James, Y., Kim, P. D., Hauser, M. A., Grünblatt, E., Moran, L. B., Mandel, S. A., Riederer, P., Miller, R. M., Federoff, H. J., Wüllner, U., Papapetropoulos, S., Youdim, M. B., Cantuti-Castelvetri, I., Young, A. B., Vance, J. M., Davis, R. L., Hedreen, J. C., Adler, C. H., Beach, T. G., Graeber, M. B., Middleton, F. A., Rochet, J.-C., & Scherzer, C. R., the Global PD Gene Expression (GPEX) Consortium. (2010) PGC-1a is a therapeutic target for early intervention in Parkinson’s disease Sci. Transl. Med., 2(52):52ra73.

Dumitriu, A., Pacheco, C. D., Wilk, J. B., Strathearn, K. E., Latourelle, J. C., Goldwurm, S., Pezzoli, G., Rochet, J.-C., Lindquist, S., & Myers, R. H. (2011) Cyclin-G associated kinase modifies a-synuclein expression and toxicity in Parkinson’s disease: results from the GenePD Study. Hum. Molec. Genet., in press.

Cullen, V., Sardi, S. P., Ng, J., Xu, Y.-H., Sun, Y., Tomlinson, J. J., Kolodziej, P., Kahn, I., Saftig, P., Woulfe, J., Rochet J.-C., Glicksman, M., Cheng, S. H., Grabowski, G. L., Shihabuddin, L. S., & Schlossmacher, M. G. (2011) Acid ß-glucocerebrosidase mutants linked to Gaucher disease, Parkinson’s and Lewy body dementia alter a–synuclein processing. Ann. Neurol., in press.


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