Jean-Christophe (Chris) Rochet

Active Mentor - currently hosting PULSe students for laboratory rotations and recruiting PULSe students into the laboratory; serves on preliminary exam committees

Current Research Interests:

Research in my laboratory is aimed at understanding the role of protein aggregation in neurodegenerative 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 agre-related neurodegenerative disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Alzheimer's disease. Our research objectives are as follows: (i) Identify molecular mechanisms underlying protein misassembly in PD and AD​. (ii) Determine how post-translational modifications affect protein aggregation in PD and AD. (iii) Identify cellular pathways perturbed by protein aggregates. (iv) Elucidate mechanisms underlying the prion-like spreading of protein aggregates throughout the brain. (v) Develop therapeutic strategies to alleviate pathology and neurodegeneration.​(vi) Develop new methods and models to investigate protein aggregation​. These questions are addressed using an interdisciplinary approach, including biochemical and biophysical analyses of recombinant proteins and the development of cellular models (e.g. primary rodent neuronal cultures, human iPSC-derived neurons) as well as in vivo models (e.g. rats injected in the brain with viral vectors or preformed amyloid-like fibrils). Finally, an important goal is to identify chemical entities (e.g. small molecules, peptidomimetics) to study and ultimately treat these devastating illnesses. Our research benefits from collaborations with experts in engineering, data science, and human medicine in the rich scientific environment provided by the Purdue Institute for Integrative Neuroscience.

Selected Publications:

Cooper, A. A., Gitler, A. D., Cashikar, A., Haynes, C. M., Hill, K. J., Bhullar, B., Liu, K., Xu, K., Strathearn, K. E., Liu, F., Cao, S., Caldwell, K. A., Caldwell, G. A., Kolodner, R. D., LaBaer, J., Rochet, J.-C., Bonini, N. M., and Lindquist, S. (2006) Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science, 313, 324-328.

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

Liu, F., Nguyen, J. L., Hulleman, J. D., Li, L., and 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., and Rochet, J.-C. (2008) Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson’s-related insults. Free Radic. Biol. Med., 45, 242-255.

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., and 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.

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., and Scherzer, C. R., the Global PD Gene Expression (GPEX) Consortium. (2010) PGC-1-alpha 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., and Myers, R. H. (2011) Cyclin-G associated kinase modifies alpha-synuclein expression and toxicity in Parkinson’s disease: results from the GenePD Study. Hum. Molec. Genet., 20, 1478-87.

Madian, A. G., Hindupur, J., Hulleman, J. D., Diaz-Maldonado, N., Mishra, V. R., Guigard, E., Kay, C. M., Rochet, J.-C.*, and Regnier, F. E.* (2012) Effect of single amino acid substitution on oxidative modifications of the Parkinson’s disease-related protein, DJ-1. Mol. Cell. Proteomics, 11(2), M111.010892.

*Co-corresponding authors. Tardiff, D. F., Jui, N. T., Khurana, V., Tambe, M. A., Thompson, M. L., Chung, C. Y., Kamadurai, H., Kim, H.-T., Lancaster, A. K, Caldwell, K. A., Caldwell, G. A., Rochet, J.-C., Buchwald, S. L., and Lindquist, S. (2013) Phenotypic screening and chemical genetics reveal a “druggable” Rsp5/Nedd4 network that ameliorates alpha-synuclein toxicity. Science 342, 979-983.

Strathearn, K. E., Yousef, G. G., Grace, M. H., Roy, S. L., Tambe, M. A., Ferruzzi, M. G., Wu, Q.-L., Simon, J. E., Lila, M. A., and Rochet, J.-C. (2014) Neuroprotective effects of anthocyanin- and proanthocyanidin-rich extracts in cellular models of Parkinson’s disease. Brain Res. 1555, 60-77. Ysselstein, D., Joshi, M., Mishra, V., Griggs, A. M., Asiago, J. M., McCabe, G. P., Stanciu, L. A., Post, C. B., and Rochet, J.-C. (2015) Effects of impaired membrane interactions on alpha-synuclein aggregation and neurotoxicity. Neurobiol. Dis. 79, 150-163

de RUS Jacquet*, A., Timmers, M., Ma, S. Y., Thieme, A., McCabe, G. P., Vest, J. H. C., Lila, M. A., and Rochet, J.-C.* (2017) Lumbee traditional medicine: neuroprotective activities of medicinal plants used to treat Parkinson’s disease-related symptoms. J. Ethnopharmacol., 206, 408-425.

*Co-corresponding authors. Mittal, S., Bjørnevik, K, Im, D. S., Flierl, A., Dong, X., Locascio, J. J., Abo, K. M., Long, E., Jin, M., Xu, B., Xiang, Y. K., Rochet, J. C., Engeland, A., Rizzu, P., Heutink, P., Bartels, T., Selkoe, D. J., Caldarone, B. J., Glicksman, M. A., Khurana, V., Schüle, B., Park, D. S., Riise, T., Scherzer, C. R. (2017). Beta-2-adrenoreceptor is a regulator of the alpha-synuclein gene driving risk of Parkinson’s disease. Science 357, 891-898.

Ysselstein, D., Dehay, B., Costantino, I. M., McCabe, G. P., Frosch, M. P., George, J. M., Bezard, E., and Rochet, J.-C. (2017) Endosulfine alpha inhibits membrane-induced alpha-synuclein aggregation and protects against alpha-synuclein neurotoxicity. Acta Neuropathol. Commun. 5(1):3. doi: 10.1186/s40478-016-0403-7.

Ambaw, A., Zheng, L., Tambe, M. A., Strathearn, K. E., Acosta , G., Hubers, S. A., Liu, F., Herr, S. A., Tang, J., Truong, A., Walls, E., Pond, A., Rochet, J.-C., and Shi, R. (2018) Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: implications for Parkinson’s disease. Mol. Cell. Neurosci. 88, 70-82.

Lv Z., Hashemi, M., Banerjee, S., Zagorski, K., Rochet, J.-C., and Lyubchenko, Y. L. (2019) Assembly of alpha-synuclein aggregates on phospholipid bilayers. Biochim. Biophys. Acta Proteins Proteom.1867, 802-812.

Sanyal, A.*, Dutta, S.*, Camara, A., Chandran, A., Koller, A., Watson, B. G., Sengupta, R., Ysselstein, D., Montenegro, P., Cannon, J., Rochet, J-C., and Mattoo S. (2019) Alpha-synuclein is a target of Fic-mediated adenylylation/AMPylation: possible implications for Parkinson's disease. J. Mol. Biol., 431, 2266-2282.

*Co-first authors. Solti, K., Kuan, W. L., Forizs, B., Kustos, G., Judith, M., Varga, Z., Herberth, B., Moravcsik, É., Kiss, R., Kárpáti, M., Mikes, A., Zhao, Y., Imre, T., Rochet, J.-C., Aigbirhio, F., Williams-Gray, C. H., Barker, R. A., and Toth, G. (2020) DJ-1 can form beta-sheet structured aggregates that co-localize with pathological amyloid deposits. Neurobiol. Dis., 134, 104629.

Landeck, N.#, Strathearn, K. E.#, Ysselstein, D.#, Buck, K., Dutta, S., Banerjee, S., Lv, Z., Hulleman, J. D., Hindupur, J., Lin, L.-K., Padalkar, S., McCabe, G. P., Stanciu, L. A., Lyubchenko, Y. L., Kirik, D.*, and Rochet, J.-C.* (2019) Two C-terminal sequence variations determine differential neurotoxicity between human and mouse alpha-synuclein. bioRxiv doi: 10.1101/700377. #Equal contribution. *Co-corresponding authors.