Professor

Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
John D. Van Nuys Medical Science Building
635 Barnhill Drive, Room 4079A
Indianapolis, Indiana 46202-5126

Phone: (317) 274-1585
Facsimile: (317) 274-4686
E-mail: adepaoli@iupui.edu

Ph. D. in Biological Sciences, 1972, University of Siena, Siena, Italy

Area of Study

Structure, function, and regulation of protein phosphatases; study of role in diabetes and obesity through knockout and transgenic overexpressing mice. More details...

Selected Recent Publications

Pathak A, del Monte F, Zhao W, Schultz JE, Lorenz JN, Bodi I, Weiser D, Hahn H, Carr AN, Syed F, Mavila N, Jha L, Qian J, Marreez Y, Chen G, McGraw DW, Heist EK, Guerrero JL, DePaoli-Roach AA, Hajjar RJ, Kranias EG. (2005) Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase 1. Circ. Res. 96, 756-766.

Pederson, B.A., Cope, C.R., Schroeder, J.M., Smith, M.W., Irimia, J.M, Thurderg, B.L., Anna A. DePaoli-Roach, A.A. and Roach, P.J. (2005) Exercise capacity of mice genetically lacking muscle glycogen synthase; in mice, muscle glycogen is not essential for exercise. J. Biol. Chem. 20, 17260-17265.

Pederson, B.A., Cope, C.R., Schroeder, J.M., Thurderg, B.L., Anna A. DePaoli-Roach, A.A. and Roach, P.J. (2005) Mice with elevated muscle glycogen stores do not have improved exercise performance. Biochem Biophys. Res. Comm. 331, 491 -49

Kirchhefer,U., Baba, H.A., Bokník, P., Breeden, K.M., Mavila,N., Brüchert,N., Larry R. Jones, Justus, I., Matus, M., Schmitz,W., DePaoli-Roach, A.A.*, and Neumann, J. * (2005) Enhanced Cardiac Function in Mice Overexpressing Protein Phosphatase Inhibitor-2. Cardiovasc. Res.68, 98-108. *Corresponding authors

Pederson, B.A., Schroeder, J.M., Parker, G.E., Smith, M.W., DePaoli-Roach, A.A. and Roach (2005) Glucose metabolism in mice lacking muscle glycogen synthase. Diabetes, 54, 3466-3473.

Wilson, W. A., Skurat, A. V., Probst, B., DePaoli-Roach, A. A., Roach, P. J. and Rutter, J. (2005) Control of mammalian glycogen synthase by PAS kinase. Proc. Natl. Acad. Sci. U.S.A. 102, 16596-16601

Jeoung, M.H., Wu, P., Joshi, M.A., Jaskiewicz, J., Bock, C.B., DePaoli-Roach, A.A., and Harris, R.A. (2006) Role of Pyruvate Dehydrogenase Kinase 4 (PDK4) in Glucose Homeostasis During Starvation. Biochem. J. 397, 417-425

Wang, W., Parker, G.E.., Skurat, A.V., Raben, N., DePaoli-Roach, A.A. and Roach, P.J. (2006). Relationship between glycogen accumulation and the laforin dual specificity phosphatase. Biochem. Biophys. Res. Comm. 350, 588-92.

Wang, W., Lohi, H., Skurat,A.V., DePaoli-Roach, A.A., Minassian, B.A. and Roach, P.J. (2007) Glycogen metabolism in tissues from a mouse model of Lafora disease. Arch. Biochem. Biophys. 457, 264-269

Hurley, T.D., Yang, J., Zhang, L., Goodwin, K.D., Zou, Q., Cortese, M., Dunker, A.K. and DePaoli-Roach, A.A. (2007) Structural Basis for regulation of Protein Phosphatase 1 by Inhibitor-2. J. Biol. Chem. 282, 28874-83.

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. PNAS. 104, 19262-6.

Savage, D.B., Zhai, L., Ravikumar, B., Choi, C.S., Snaar, J.E.M., McGuire, A.C., Wou, S.E., Medina-Gomez, G., Kim, S., Bock, C.B., Segvich, D.M., Vidal-Puig, A., Wareham, N.J., Shulman, G.I., F Karpe, F., Taylor, R., Pedersen, B.A., Roach, P.J., O'Rahilly, S. and DePaoli-Roach, A.A. (2008) A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. PloS Medicine, 5, e27.

Brüchert, N., Mavila, N., Boknik, P., Baba , H.A., Fabritz., L., Gergs, U., Kirchhefer, U., Kirchhof, P., Matus,M., Schmitz, W., *DePaoli-Roach, A.A. and *Neumann, J.. (2008). Inhibitor-2 prevents phosphatase 1 induced cardiac hypertrophy and mortality. Amer. J. Physiol. In press.

Eckerdt F, Pascreau G, Phistry M, Lewellyn AL, DePaoli-Roach AA and Maller JL. (2009). Phosphorylation of TPX2 by Plx1 enhances activation of Aurora A. Cell Cycle, 8:2413-9.

Irimia J.M., 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.

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 U S A. 2010 Oct 12;107(41):17563-8. Epub 2010 Sep 27. PubMed PMID: 20876143128.

DePaoli-Roach, A.A.*, Tagliabracci, V.S., Segvich, D.M., Meyer, C.M., Jose 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. 2010 Aug 13;285(33):25372-81. Epub 2010 Jun 10. PubMed PMID: 20538597; PubMed Central PMCID: PMC2919100.

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. J Biol Chem. 2010 Sep 1. [Epub ahead of print] PubMed PMID: 20810658.

Cheng, G., Takahashi, M., Shunmugavel , A., Wallenborn, J.G., DePaoli-Roach, A.A., Gergs, U., Neumann, J., Kuppuswamy, D., Menick, D.R., and Cooper, G. IV. Basis for MAP4 dephosphorylation-related microtubule network densification in pressure overload cardiac hypertrophy. J Biol Chem. 2010 Dec 3;285(49):38125-40 PubMed PMID: 20889984.

Vincent S. Tagliabracci, V.S., Heiss, C., Glushka, J., Karthik, C., Mayumi Ishihara, M., Parastoo Azadi, P., Hurley, T.D.,
DePaoli-Roach, A.A., and Roach, P.J. (2011) Phosphate Incorporation during Glycogen Synthesis Underlies Lafora Disease. Cell Metab. 2011 Mar 2;13(3):274-82. PMID:21356517.

Turnbull. J., DePaoli-Roach A.A.*, Zhao, X, Miguel A Cortez, M.A., Piliguian, M., Pencea, N., Tiberia, E., Wang, P., Roach, P.J., Ackerley, C.A., and Minassian, B.A.* (2011) PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease. Plos Genetic, in press.

Raman, M., Zhang, K., Earnest, S., Juang, Y-C., DePaoli-Roach, A.A., Zhao, Y., and Cobb, M.H. (2010) The regulatory subunit PPP1R7 binds TAO3 and is involved in the response to DNA damage. Under revision for JBC.

*Corresponding authors

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Research Interests

The major interest of our research centers on structure-function relationship and physiological role of type 1 serine/threonine protein phosphatases (PP1) with a particular emphasis on glycogen metabolism and hence diabetes and obesity. The properties of the PP1 enzymes are determined by association with various regulatory/targeting subunits that direct the enzyme to different subcellular locals, confer substrate specificity and regulate activity. To date, more that 100 PP1-binding protein have been identified, among which are inhibitors, such as inhibitor-1 and -2 and glycogen targeting subunits, such as RGL and PTG, that have been implicated in insulin control of glycogen metabolism. Inhibitor-2 forms a stable complex with the catalytic subunit of PP1c that undergoes cyclic inactivation/reactivation. In collaboration with Dr. Thomas Hurley we have recently solved the structure of the complex, which provides insights into the molecular mechanism of inhibition and reactivation of the phosphatase. The structure is also consistent with analyses of prediction of disordered regions in inhibitor-2 as well as interaction domains. The role of the glycogen-associated phosphatases has been addressed in overexpressing and knockout mice. Glycogen metabolism is controlled by phosphorylation of the key glycogen metabolizing enzymes, glycogen synthase, glycogen phosphorylase and phosphorylase kinase that are bound to glycogen and are dephosphorylated by glycogen-associated forms of PP1. In skeletal muscle four glycogen-targeting subunits are expressed, RGL/GM which is the most abundant, PTG/R5, R6 and possibly R3E. Our laboratory has shown that disruption of the RGL gene (PPP1R3A) results in ~90% reduction of glycogen without affecting whole body glucose homeostasis. The animals do not become obese and appear to utilize more fatty acids. On the other hand, mice overexpressing RGL accumulate glycogen 3-5-fold over basal and become insulin resistant. These studies indicate that decreased muscle glycogen stores may cause a metabolic switch to increase fatty acid utilization, whereas muscle glycogen overaccumulation results in increased intramyocellular lipids and insulin resistance.

It has been reported that, in a human population, individuals that carry a double mutation in the PPARgamma and the RGL genes develop severe insulin resistance. In attempts to recapitulate the human phenotype, we have introduced in mice the same mutation found in the human RGL. RGL-kin mice exhibit significantly lower glycogen synthase -/+ G-6P activity ratio and muscle glycogen content than WT littermates. When PPARgamma +/- mice were crossed with the RGL-kin heterozygotes, the doubly heterozygous animals show normal glucose tolerance and insulin sensitivity. Interestingly, human heterozygous carriers of the mutation, which is present in ~1% of UK Caucasians, as well as double heterozygotes also have significantly reduced basal and postprandial muscle glycogen. However, reduced muscle glycogen by itself has not effect on glucose homeostasis either in mice or in humans. Further support that decreased glycogen does not induce insulin resistance comes from our studies on PTG knockout mice. Although it had previously been reported that PTG null mice are not viable and that the heterozygous become insulin resistant, the mice generated in our laboratory are viable and surprisingly more insulin sensitive as determined by glucose and insulin tolerance tests as well as hyperinsulinemic-euglycemic clamps. In addition the null mice exhibit increased energy expenditure and elevated serum adiponectin. Altogether, these studies indicate that by itself reduced glycogen accumulation in various tissues has no deleterious effect on whole body glucose homeostasis and insulin sensitivity.

PP1 plays a major role in control of cardiac function. We have shown that transgenic mice overexpressing the catalytic subunit of PP1 in heart exhibit cardiac muscle hypertrophy and heart failure. Furthermore, in collaborative studies we have demonstrated that overexpression of two PP1 inhibitors, inhibitor-1 and 2, results in decreased PP1 activity and enhanced contractility in the heart, underscoring the fundamental role of PP1 in cardiac function. More recently we have shown that overexpression of I-2 rescues the cardiac defect of the PP1c mice, suggesting that inhibition of PP1 may represent a potential target for treatment of dilated cardiomyopathy and heart failure.