Distinguished Professor,
Chancellor's Professor,
Director of Center for Diabetes Research

Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
John D. Van Nuys Medical Science Building
635 Barnhill Drive, Room 405A
Indianapolis, Indiana 46202-5126

Phone: (317) 274-1582
Facsimile: (317) 274-4686
E-mail: proach@iupui.edu

B.S. in Biochemistry, 1969, University of Glasgow, Scotland
Ph.D. in Biochemistry, 1972, University of Glasgow, Scotland
Postdoctoral Fellow, 1972-1974, University of California, Los Angeles, CA
Postdoctoral Fellow, 1974-1975, University of Virginia, Charlottesville, VA

Area of Study

Glycogen metabolism and its regulation. Covalent phosphorylation of glycogen, its metabolism and Lafora disease. Vesicular trafficking of glycogen to the lysosome and autophagy. Mouse models with genetically modified glycogen stores and blood glucose homeostasis.  More details...

Selected Recent Publications

Tagliabracci, V.S., Turnbull, J., Wang, W., Girard, J.-M., Zhao, X., Alexander V. 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

Tagliabracci, V.S., Girard, J.-M., Segvich, D., Meyer, C., Turnbull, J., Zhao, X., Minassian, B., DePaoli Roach, A.A. and Roach, P.J. (2008) Abnormal metabolism of glycogen phosphate as a cause for Lafora Disease J. Biol. Chem. 283, 33816-25

Heyen, C.A., Tagliabracci, V.S., Zhai, L. and Roach, P.J. (2009) Characterization of Mouse UDP-glucose Pyrosphosphatase, a Nudix Hydrolase encoded by the Nudt14 Gene. Biochem. Biophys. Res. Commun. 390, 14-8 PMID: 19896456

Irimia-Dominguez, J., Meyer, C.M., Peper, C.L., Zhai, L., Bock, C.B., Previs, S.F., McGuinness, O.P., DePaoli-Roach, Anna A., and Roach, P.J. (2010) Impaired Glucose Tolerance and Predisposition to the Fasted State in Liver Glycogen Synthase Knockout Mice. J. Biol. Chem. 285, 12851-61 PMID: 20178984

Wilson, W.A., Boyer, M.P., Davis, K.D., Burke, M., and Roach, P.J. (2010) The subcellular localization of yeast glycogen synthase is dependent upon glycogen content. Canadian J. Microbiol. 56, 408-20 PMID: 20555403

Baskaran, S., Roach, P.J., DePaoli-Roach, A.A. and Hurley, T.D. (2010) Structural basis for glucose-6-phosphate activation of glycogen synthase Proc. Natl. Acad. Sci. USA 107, 17563-8 PMID: 20876143

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 PMID: 20538597

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 PMID: 20724661

Jiang, S., Heller, B., Tagliabracci, V.S., Zhai, L., Irimia, J.M., DePaoli-Roach, A.A., Wells, C.D., Skurat, A.V., and Roach, P.J. (2010) Starch binding domain containing protein 1/genethonin 1 is a novel participant in glycogen metabolism J. Biol. Chem. 85, 34960-71 PMID: 20810658

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

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Research Interests

Our research has centered on the study of glycogen metabolism and its regulation, in mammals and yeast. Glycogen is a branched polymer of glucose that serves as a repository of energy and carbon. In mammals, the two largest deposits of glycogen are the skeletal muscle and liver, which express different isoforms of glycogen synthase. After a meal, ingested glucose is converted into glycogen, in skeletal muscle and liver. Derangement of glycogen metabolism is associated with metabolic disease, diabetes and several rarer glycogen storage diseases. Our research has always taken a multi-faceted approach, using biochemical, structural, cellular and whole animal systems to address fundamental mechanisms. We are actively engaged in the study of several mouse models in which the gene for either the liver or muscle isoform of glycogen synthase is knocked out, examining the associated changes in whole body glucose metabolism.

Currently, we are excited about two novel and relatively unexplored areas of glycogen metabolism. The first addresses Lafora disease, a deadly form of childhood epilepsy, caused by mutations to one of two genes, Epm2a or Epm2b, which encode respectively laforin, a glycogen phosphatase, or malin, an E3 ubiquitin ligase. In Lafora disease, deposits of poorly branched glycogen accumulate as Lafora bodies in many tissues including neurons. We showed that laforin is a glycogen phosphatase that removes the low levels of covalent phosphate normally present in glycogen. In its absence, glycogen becomes hyperphosphorylated and its structure becomes abnormal and toxic. We showed that the phosphate in glycogen derives from errors by the main catalytic enzyme glycogen sythnase, which occasionally, 1 in 10,000 catalytic cycles, introduces glucose phosphate rather than glucose. This may be considered an error in polysaccharide biosynthesis and laforin can be viewed as a glycogen repair enzyme. The function of malin, however, is still not understood. We are actively studying malin and were the first to produce malin knockout mice that we are now investigating. We are also interested in the possible relationship between autophagy and Lafora disease.

Textbooks focus on the degradation of glycogen by a cytosolic process involving glycogen phosphorylase in response to hormonal cues or muscular activity. However, glycogen is also disposed by transport to the lysosome by a poorly understood autophagy-like process. The importance is underscored by Pompe disease in which the lysosomal a-glucosidase is defective. The most severe forms of Pompe disease are fatal within the first year after birth. We have shown that a previously unstudied protein, Stbd1, may be involved in the vesicular trafficking of glycogen to the lysosome. We have further identified GABARAPL1, a known autophagy protein, as an Stbd1 interacting protein. It is an ortholog of the better studied LC3 autophagy protein. We hope to understand better the mechanism by which glycogen is transferred to the lysosome and we are in the process of generating Stbd1 knockout mice.