Roach Lab

Primary Dept. — Biochemistry and Molecular Biology

The research lab of Peter J. Roach, PhD is primarily focused on the metabolism of glycogen, its regulation, and the clinical consequences of its defects, as exhibited in glycogen storage diseases (glycogenoses). The approaches used include biochemical analysis of glycogen and related enzymes, genetically modified mouse lines, screening for inhibitors of glycogen accumulation in cells and, in collaboration with Thomas Hurley, PhD, analysis of relevant protein structures.

Glycogen, Glycogenoses and Lafora Disease

Glycogen is a branched polymer of glucose that acts as a reserve of glucosyl units, to be used for anabolism or as a source of energy. In mammals, the major deposits are skeletal muscle and liver, but glycogen is found in other tissues, including brain. In all tissues, it is believed to provide an energy buffer, laid down in times of nutritional plenty for utilization in times of need. Study of the enzymes of glycogen metabolism contributed much to the lab’s knowledge of enzyme regulation and signal transduction.

Glycogenoses

Genetic defects in a several genes, some known for decades and others discovered more recently, can lead to abnormalities in glycogen structure and/or accumulation. Usually, there is an over-accumulation of glycogen. Investigators in this lab are interested mainly in three of these glycogen storage diseases: Pompe Disease (GSD II), Cori Disease (GSD III) and Lafora disease. The Roach Lab has shown that genetic depletion of glycogen accumulation in mouse models of glycogenoses can correct pathological consequences of the aberrant glycogen storage. These results suggest a possible therapeutic approach to treat glycogenoses: suppress glycogen accumulation in tissues.

Lafora Disease

Only recently recognized as a glycogen storage disease, Lafora Disease—a rare but fatal teenage-onset epilepsy—is still poorly understood, and no treatment is available. Initial symptoms are usually observed in early teenage years followed by gradual neurological decline and death normally within ten years.

Mutations in either of two genes, EPM2A or EPM2B, cause almost all cases of Lafora Disease. The genes encode respectively laforin, a glycogen binding protein with dual-specificity phosphase activity, and malin, an E3 ubiquitin ligase. Their functions are not well-understood. However, mutation of either leads to a very similar disease in which glycogen structure is defective, being less branched, less soluble and more phosphorylated. Part of the research program in the Roach Lab seeks to understand the functions of laforin and malin.

Glycogen Suppression Therapy

Because genetic depletion of glycogen in mice can ameliorate symptoms of glycogenoses, the Roach Lab scientists developed a program to search for small molecules that could suppress glycogen storage. Attention is directed to inhibitors of the synthetic enzyme glycogen synthase or its activating protein phosphase (PP1/PTG). The lab developed assays for high and medium throughput screening and has analyzed close to 80,000 compounds from available chemical libraries. This group of scientists have several leads whose properties they are attempting to refine.

Current Research Funding

Small Molecule Inhibition of Glycogen Storage as Therapy of Glycogenoses

Suppression of glycogen accumulation is a promising therapeutic approach to combat glycogenoses, and in particular Pompe disease

Suppressing glycogen storage with small molecule inhibitors as a therapeutic approach to LD

Define the clinical biochemistry of LD mutations to provide a personalized diagnosis and establish therapeutic options to treat LD, ultimately resulting in a cure

Glycogen Metabolism and Lafora Disease

Understand the molecular basis for the myoclonic epilepsy of Lafora (epilepsy, progressive myoclonus, type 2, EPM2) and the role of abnormal glycogen metabolism in the disease.

Recent Publications

A full listing of publications by Peter Roach, PhD, is available on PubMed.

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

Mahalingan KK, Baskaran S, DePaoli-Roach AA, Roach PJ, Hurley TD. (2017) Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation. Biochemistry. Jan 10;56(1):179-188. doi: 10.1021/acs.biochem.6b00884. Epub 2016 Dec 20. PubMed PMID: 27935293.

Skurat AV, Segvich D, DePaoli-Roach AA, Roach PJ. Novel method for detection of glycogen in cells (2017) Glycobiology. 2017 May 1;27(5):416-424. doi: 10.1093/glycob/cwx005. PMID: 28077463

Irimia JM, Meyer CM, Segvich DM, Surendran S, DePaoli-Roach AA, Morral N, Roach PJ. Lack of liver glycogen causes hepatic insulin resistance and steatosis in mice. J Biol Chem. 2017 Jun 23;292(25):10455-10464. doi: 10.1074/jbc.M117.786525. PMID: 28483921

Gentry MS, Guinovart JJ, Minassian BA, Roach PJ, Serratosa J. Lafora disease offers a unique window into neuronal glycogen metabolism.J Biol Chem. 2018 Feb 26. pii: jbc.R117.803064. doi: 10.1074/jbc.R117.803064. [Epub ahead of print] PMID: 29483193

Research Team

Peter J. Roach, PhD

Peter J. Roach, PhD

Distinguished Professor
Alexandre V. Skurat, PhD

Alexandre V. Skurat, PhD

Associate Research Professor of Biochemistry & Molecular Biology

Additional Research Team Members

Other lab team members include Dyann Segvich (laboratory manager), Christopher Contreras (post-doctoral fellow) and Safnas Abdul Salam (post-doctoral fellow).