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Peter Roach, Ph.D.

Chancellor's Professor
Distinguished Professor, Biochemistry & Molecular Biology

Education/Training:
Ph.D., Biochemistry, University of Glasgow, Scotland (1972)
Postdoctoral, Metabolic Regulation, University of California, Los Angeles, CA (1974)
Postdoctoral, Hormonal Regulation, University of Virginia, Charlottesville, VA (1975)
Fellow, Biochemistry, Scuola Normale Superiore di Pisa, Italy (1977) 

Research:
My research has focused on glycogen metabolism which early in my career provided some of the best examples of the control of protein function by reversible covalent phosphorylation, now known to be a common and widespread process.  I have studied this mechanism, and the protein kinases involved, mainly focusing on the biosynthetic enzyme glycogen synthase using biochemical, molecular biological and genetic approaches.  Quite recently, we became interested in the significance of the small amount of covalent phosphate associated with glycogen.  This interest has led us to a rare neurological disease, Lafora disease, named for the Spanish physician who first described it more than a century ago.  Lafora disease is a monogenic, autosomal recessive disorder.  The vast majority of cases can be attributed to mutations in either of two genes, EPM2A or EPM2B, which encode, respectively, laforin and malin.  Onset is generally in the mid-teens, usually heralded by a major epileptic incident.  Gradual neurological decline follows and afflicted individuals normally succumb within ten years.  There is no cure for this harrowing condition (https://www.chelseashope.org/). 

Laforin, by amino acid sequence, is a member of the dual specificity protein phosphatase family, unique in that it contains a built-in polysaccharide binding module.  In fact, we believe that its physiological substrate is actually the covalent phosphate of glycogen - glycogen from laforin knockout mice contains elevated amounts of phosphate.  The phosphate, we believe, perturbs glycogen structure, renders it less soluble in water and less metabolizable, resulting ultimately in the overaccumulation of abnormal glycogen in tissues.  These deposits, first described by Lafora, also bear his name - Lafora bodies.  They are composed largely of glycogen, which besides being hyperphosphorylated is also less branched than normal glycogen.  In neurons, Lafora bodies are believed to cause cell death and thus promote the neurodegeneration of the disease.

From other studies of glycogen metabolism, we have available genetic mouse models in which glycogen levels are either depleted or eliminated.  When we crossed one of these lines, PTG-/- mice, with laforin knockout mice, we were able to normalize the level of brain glycogen, eliminate Lafora body formation and alleviate some disease markers.  With this genetic proof-of-principle, we have initiated a program to screen for small molecule suppressors of glycogen storage, with most attention directed towards glycogen synthase.  With a newly developed assay, we have embarked on high throughput screening of compound libraries to identify glycogen synthase inhibitors.  This work, a joint project with my long-term collaborators Anna DePaoli-Roach and Tom Hurley, is ongoing and we are excited by early results.  The same principle, suppression of glycogen accumulation, is also potentially applicable to other glycogen storage diseases, notably Pompe disease in which muscle and/or heart are the primary affected organs.

Search for Dr. Roach on PubMed

Publications:

Lafora Disease, Glycogen Phosphorylation and Glycogenoses.

1.      Tagliabracci, V.S., Turnbull, J., Wang, W., Girard, J.-M., Zhao, X., Skurat, A.V., Delgado-Escueta, A.V., Minassian, B.A., DePaoli-Roach, A.A., and Roach, P.J. (2007) Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo. Proc. Nat. Acad. Sci. USA 104, 19262-6 PMCID: PMC2148278

2.      Douillard-Guilloux, G., Raben, N., Takikita, S., Ferry, A., Vignaud, A., Guillet-Deniau, I., Favier, M., Thurberg, B.L., Roach, P.J., Caillaud, C. and Richard, E. (2010) Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease.  Human Mol. Gen. 19, 684-96  PMID: 19959526

3.      DePaoli-Roach, A.A., Tagliabracci, V.S., Segvich, D.M., Meyer, C.M., Irimia, J.M., and Roach, P.J. (2010) Genetic depletion of the malin E3 ubiquitin ligase in mice leads to Lafora bodies and the accumulation of insoluble laforin J. Biol. Chem. 28, 25372-81 PMCID: PMC2919100

4.      Tagliabracci, V.S., Heiss, C., Karthik, C., Contreras, C.J., Glushka, J., Ishihara, M, Azadi, P., Hurley, T.D., DePaoli-Roach, A. A., and Roach, P.J. (2011) Phosphate Incorporation during Glycogen Synthesis and Lafora Disease Cell Metabolism 13, 274-282 PMCID: PMC2966110

5.      Turnbull, J., Depaoli-Roach, A. A., Zhao, X., Cortez, M. A., Pencea, N., Tiberia, E., Piliguian, M., Roach, P. J., Wang, P., Ackerley, C. A., and Minassian, B. A. (2011) PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease PLoS Genet 7, e1002037 PMCID: PMC3084203

6.      DePaoli-Roach, A.A., Segvich, D.M., Meyer, C.M., Rahimi, Y., Worby, C.A. Gentry, M.S., and Roach, P.J. (2012) Laforin and malin knockout mice have normal glucose disposal and insulin sensitivity Hum. Mol. Genet. 21, 1604-10

7.      Pederson, B.A., Turnbull, J., Epp, J.R., Weaver, S.W., Zhao, X., Pencea, N., Roach, P.J., Frankland, P., Ackerley, C.A., and Minassian, B.A. (2013) Inhibiting glycogen synthesis prevents Lafora disease in a mouse model. Annals Neurol. 74, 297-300

8.      Chikwana, V. M., Khanna, M., Baskaran, S., Tagliabracci, V.S., Contreras, C.J., DePaoli-Roach, A.A., Roach, P.J., and Hurley, T.D.(2013). The structural basis of 2-phosphoglucose incorporation into glycogen by glycogen synthase. Proc Natl Acad Sci, USA 110: 20976-20981.

9.      Garyali, P., Segvich, D.M., DePaoli-Roach, A.A. (2014). Protein degradation and quality control in cells from laforin and malin knockout mice. J Biol Chem. 289, 20606-14

10.    DePaoli-Roach, A.A., Contreras, C.J., Segvich, D.M., Heiss, C., Ishihara, M., Azadi, P., Roach P.J. (2015) Glycogen phosphomonoester distribution in mouse models of the progressive myoclonic epilepsy, Lafora disease.  J. Biol. Chem. 290, 841-50

11.    Irimia, J. M., Tagliabracci, V. S., Meyer, C. M., Segvich, D. M., DePaoli-Roach, A. A., and Roach, P. J. (2015) Muscle Glycogen Remodeling and Glycogen Phosphate Metabolism following Exhaustive Exercise of Wild Type and Laforin Knockout Mice. J Biol Chem 290, 22686-22698

12.    Contreras, C.J., Segvich, D.M., Mahalingan, K., Chikwana, V.M., Kirley, T.L., Hurley, T.M., DePaoli-Roach, A.A., and Roach, P.J. (2016) Detection of phosphate incorporation into glycogen by glycogen synthase 597, 21-9 PMID: 27036853

Recent Reviews and commentaries.

1.      Tagliabracci, V.S., and Roach, P.J. (2010) Insights into the mechanism of polysaccharide dephosphorylation by a glucan phosphatase. Proc. Natl. Acad. Sci. USA 107, 15312-3 PMCID: PMC2932587

2.      Roach, P.J. (2011) Are there errors in glycogen biosynthesis and is laforin a repair enzyme?  FEBS Letters 585, 3216-8 PMID: 21930129

3.      Roach, P.J., DePaoli-Roach, A. A., Hurley, T. D. and Tagliabracci, V. S. (2012) Glycogen and its metabolism: Some new developments and old themes Biochem. J. 441, 763-87

4.      Roach, P.J. and DePaoli-Roach, A.A. (2013) Glycogen metabolism and Lafora disease in Protein Tyrosine Phosphatase Control of Metabolism (K.K. Bence Ed.) Springer, New York pp239-262

5.      Roach, P.J. (2013) Glycogen Metabolism in "Encyclopedia of Biological Chemistry" Vol. 2, 2nd edition (W. J. Lennarz and M. D. Lane eds) Elsevier Science. San Diego pp 425-7

6.      Roach, P. J. (2015) Glycogen phosphorylation and Lafora disease. Molecular Aspects of Medicine 46, 78-84 PMID: 26278984

7       Roach, P.J. and Zeeman, S.C. (2016) Glycogen and starch. Encyclopedia of Cell Biology, Volume 1, Elsevier, Waltham, MA (Bradshaw R.A. and Stahl, P.D. eds) pp 263-270

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