Jiyan Ma

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Associate Professor

Ph.D. - University of Illinois, Chicago
Post Doctoral - University of Chicago

The main focus of the laboratory is to elucidate the pathogenic mechanism of the Transmissible Spongiform Encephalopathies (TSEs), also known as prion disease. The uniqueness of TSEs is that these neurodegenerative diseases are bona fide infectious diseases with an unusual infectious agent, the prion.

The normal prion protein, PrP, is a cell surface localized cellular glycoprotein. During prion disease, a portion of PrP changes to a conformation called PrPSc, which is aggregated and protease resistant. According to the prion theory, the aberrantly folded PrPSc form can recruit normal PrP into the PrPSc conformation and lead to neurotoxicity. It has been established that the PrP expression is required for the development of prion disease, but the molecular mechanisms behind prion infectivity and neurodegeneration remain unclear, preventing us to develop effective prophylactic, diagnostic and therapeutic strategies. We are investigating the pathogenic mechanism of prion disease using a variety of approaches, including in vitro protein folding assay, mammalian cell culture assays, animal infectivity study, and transgenic mouse models.

We recently developed an in vitro biochemical system to convert bacterially expressed recombinant PrP into the pathogenic conformation. We have identified a critical role of lipid in generating infectious prion conformation. This in vitro system allows us to study the molecular basis for prion infectivity and to develop novel diagnostic and therapeutic approaches against these fatal neurodegenerative diseases.

We are studying the mechanism responsible for the neurodegeneration in prion disease. Our studies reveal that misfolding of PrP in the endoplasmic reticulum (ER) leads to its retro-translocation to the cytosol. Using transgenic mouse models, we discover that the cytosolic accumulation of PrP causes neurodegeneration in different neurons. Our results also support that the PrP-caused membrane permeability alteration is the neurotoxic mechanism.

Prion disease is one of the many neurodegenerative diseases involving accumulation of aberrantly folded proteins such as Alzheimer’s disease and Parkinson’s disease. We are also interested in understanding the commonality and specificity of these protein-folding diseases, how these diseases occur, why these diseases occur in the neuronal system, and what is the influence of aging on these diseases.

Recent Publications:

• Wang F, Wang X and Ma J (2011) "Conversion of bacterially expressed recombinant prion protein" Methods 53(3):208-13.
• Wang F, Yin S, Wang X, Zha L, Sy MS and Ma J (2010) "Role of the highly conserved middle region of prion protein (PrP) in PrP-lipid interaction" Biochemistry 49(37):8169-76.
• Wang F, Wang X, Yuan CG and Ma J (2010) "Generating a Prion with Bacterially Expressed Recombinant Prion Protein" Science 327(5969);1132-5.
• Faas H, Jackson WS, Borkowski AW, Wang X, Ma J, Lindquist S and Jasanoff A (2010) "Context-dependent perturbation of neural systems in transgenic mice expressing a cytosolic prion protein." Neuroimage 49(3):2607-17.
• Wang X, Bowers SL, Wang F, Pu XA, Nelson RJ and Ma J (2009) "Cytoplasmic prion protein induces forebrain neurotoxicity" Biochim Biophys Acta. 1792(6):555-63.
• Cornwell DG and Ma J (2008) "Nutritional benefit of olive oil: the biological effects of hydroxytyrosol and its arylating quinone adducts" J Agric Food Chem 56(19):8774-86.
• Cornwell DG and Ma J (2007) "Studies in vitamin E: biochemistry and molecular biology of tocopherol quinones" Vitam Horm. 76:99-134.
• Wang F, Yang F, Hu Y, Wang X, Wang X, Jin C and Ma J (2007) "Lipid Interaction Converts Prion Protein to a PrP(Sc)-like Proteinase K-Resistant Conformation under Physiological Conditions" Biochemistry. 46(23):7045-53.
• Wang X, Wang F, Arterburn L, Wollmann R and Ma J (2006) "The interaction between cytoplasmic PrP and the hydrophobic lipid core of membrane correlates with neurotoxicity" J Biol Chem 281(19):13478-84.
• Wang X, Thomas B, Sachdeva R, Arterburn L, Frye L, Hatcher PG, Cornwell DG and Ma J (2006) "Mechanism of arylating quinone toxicity involving Michael adduct formation and induction of endoplasmic reticulum stress" PNAS 103(10):3604-09.
• Wang X, Wang F, Sy MS and Ma J (2005) "Calpain and other cytosolic proteases can contribute to the degradation of retro-translocated prion protein in the cytosol" J Biol Chem 280(1):317-25.
• Sachdeva R, Thomas B, Wang X, Ma J, Jones KH, Hatcher PG and Cornwell DG (2005) "Tocopherol metabolism using thermochemolysis: chemical and biological properties of gamma-tocopherol, gamma-carboxyethyl-hydroxychroman, and their quinones" Chem Res Toxicol 18(6):1018-25.
• Ma J and Lindquist S (2002) "Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol" Science 298(5599):1785-8.
• Ma J, Wollmann R and Lindquist S (2002) "Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol" Science 298(5599):1781-5.