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Matthew Gentry
Assistant Professor
B.S. University of Evansville
Ph.D. Syracuse University
Postdoctoral Fellowship University of California, San Diego

Office: 859.323.8482
Lab: 859.323.3289

Overview ▪ Recent Highlights ▪ Funding ▪ Recent Publications ▪ PubMed

Overview
Recent Highlights ▪ Funding ▪ Recent Publications ▪ PubMed

Our lab studies the role of signal transduction machinery, namely phosphatases and E3 ubiquitin ligases, in neurodegenerative disease. We utilize a multidisciplinary approach that addresses and/or employs methodologies of cell biology, biochemistry, neurodegenerative diseases, genetics, bioinformatics, and phylogenetic relationships in vertebrate and protozoan model organisms, but relies heavily on cell biology and biochemistry. These applications employ model organisms and tissue culture cells to study basic cell processes, which have direct relevance to progressive myoclonus epilepsy.

Humans develop insoluble glycogen particles, called Lafora bodies, as a result of the recessive neurodegenerative disorder called Lafora disease (LD). LD presents as a seizure in the second decade of the patient’s life and ends with death within ten years. The frequency and severity of the patient’s epilepsy increase with age and with the accumulation and size of LBs. Thus, it is hypothesized that LBs are the causative agent of the patient’s epilepsy and eventually the death of the patient. LD is the result of mutations in either the gene encoding the phosphatase laforin or the E3 ubiquitin ligase malin. The focus of our lab is to determine how the phosphatase laforin and the ubiquitin ligase malin regulate glycogen metabolism and inhibit Lafora disease.

Laforin was previously thought to only be conserved in vertebrates; however, we recently identified laforin orthologs in five unicellular eukaryotes (i.e. protists). Surprisingly, the biochemical composition of LBs closely resembles that of floridean starch; an insoluble carbohydrate synthesized by the same protists that have laforin. We demonstrated a direct correlation between the presence of laforin and synthesis of insoluble carbohydrates amongst protists. Additionally, we demonstrated that a plant protein called SEX4 is a functional equivalent of laforin. Strikingly, mutations in SEX4 result in a starch excess phenotype very reminiscent to LD. These insights led us to hypothesize that laforin is the first member of a unique group of carbohydrate phosphatases.

We also demonstrated that malin is an E3 ubiquitin ligase that polyubiquitinates multiple proteins involved in glycogen synthesis, including laforin, protein targeting to glycogen (PTG), and glycogen debranching enzyme (AGL/GDE). Polyubiquitination is a cellular signal to degrade a protein. Thus, malin decreases glycogen accumulation by promoting the degradation of these, and other proteins.

Cumulatively, we propose that malin- and laforin-like activities are involved in an unstudied aspect of carbohydrate metabolism and that these functions are conserved from plants to protists to humans.

Recent Highlights
Overview ▪ Funding ▪ Recent Publications ▪ PubMed

Our work was recently highlighted on the Howard Hughes Medical Institute website in an article entitled "Reading the Leaves for Clues to Origin of Rare Epilepsy."

In addition, our work was chosen as the cover of an issue of The Journal of Cell Biology and highlighted in the “In this Issue” section of the journal.

Funding
Overview ▪ Recent Highlights ▪ Recent Publications ▪ PubMed

Our work is funded through 2012 by the National Institute of Neurological Disorders and Stroke (NINDS), an institute within the NIH.  The project number of our work is 5R00NS061803-01 and titled, Use of Novel Model Systems Link Floridean Starch Metabolism to Lafora Disease.

Recent Publications
Overview ▪ Recent Highlights ▪ Funding ▪ PubMed

These publications are available for download and require Adobe Reader for viewing.

1. Matthew S. Gentry, Jack E. Dixon, and Carolyn A. Worby. 2009. "Lafora disease: insights into neurodegeneration from plant metabolism." Trends in Biochemical Sciences. In press.
2. Simon Hsu, Youngjun Kim, Sheng Li, Eric S. Durrant, Rachel M. Pace, Virgil L. Woods, Jr., and Matthew S. Gentry. 2009. "Structural Insights into Glucan Phosphatase Dynamics Using Amide Hydrogen-Deuterium Exchange Mass Spectrometry." Biochemistry. 48: 9891-9902. http://pubs.acs.org/doi/full/10.1021/bi9008853
3. Matthew S. Gentry and Rachel M. Pace.  2009.  "Conservation of the glucan phosphatase laforin is linked to rates of molecular evolution and the glycogen metabolism of the organism." BMC Evolutionary Biology. 9:138.
   » Click here for download (2.53MB PDF).
4. Oliver Kötting, Diana Santelia, Christoph Edner, Simona Eicke, Tina Marthaler, Matthew S. Gentry, Sylviane Comparot-Moss, Jychian Chen, Alison M. Smith, Martin Steup, Gerhard Ritte, and Samuel C. Zeeman.   2009.  "STARCH-EXCESS4 is a Laforin-like Phosphoglucan Phosphatase Required for Starch Degradation Arabidopsis thaliana." The Plant Cell. 21: 334-346.
   » Click here for download (887KB PDF).
5. Matthew S. Gentry, Seema Mattoo, and Jack E. Dixon.  2009.  "Utilizing red algae to understand a neurodegenerative disease."  In Red Algae in the Genomics Age.  Springer.  In press.
6. Carolyn A. Worby*, Matthew S. Gentry*, and Jack E. Dixon.  2008.  "Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG)."  Journal of Biological Chemistry.  283: 4069-4076.  *These authors contributed equally.
   » Click here for download (293KB PDF).
7. Alan Cheng, Mei Zhang, Matthew S. Gentry, Carolyn A. Worby, Jack E. Dixon, and Alan R. Saltiel.  2007.  "A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori disease."  Genes and Development.  21: 2399-2409.
   » Click here for download (1.09MB PDF).
8. Matthew S. Gentry, Robert H. Dowen III, Carolyn A. Worby, Seema Mattoo, Joseph R. Ecker and Jack E. Dixon.  2007.  "The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease."  The Journal of Cell Biology.  178: 477-488.
   » Click here for download (4.48MB PDF).
9. Youngjun Kim, Matthew S. Gentry, Thurl E. Harris, Sandra E. Wiley, John C. Lawrence, Jr. and Jack E. Dixon.  2007.  "A phosphatase cascade that regulates nuclear membrane biogenesis is conserved from yeast to human."  Proceedings of the National Academy of Sciences USA.  104 (16): 6596-6601.
   » Click here for download (2.17MB PDF).
10. Carolyn A. Worby, Matthew S. Gentry, and Jack E. Dixon.  2006.  "Laforin: A dual specificity phosphatase that dephosphorylates complex carbohydrates."  Journal of Biological Chemistry.  281 (41): 30412-30418.
    » Click here for download (361KB PDF).
11. Matthew S. Gentry, Richard L. Hallberg, and David C. Pallas.  2006.  "An in vivo assay to quantify stable protein phosphatase 2A (PP2A) heterotrimeric species."  Methods in Molecular Biology.  365: 71-84.
    » Click here for download (381KB PDF).
12. Matthew S. Gentry, Carolyn A. Worby, and Jack E. Dixon.  2005.  "Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin."  Proceedings of the National Academy of Sciences USA.  102 (24): 8501-8506.
    » Click here for download (367KB PDF).
13. Matthew S. Gentry, Yikun Li, Huijun Wei, Farhana Syed, Sameer H. Patel, Richard L. Hallberg and David C. Pallas.  2005.  "A novel assay for protein phosphatase 2A (PP2A) complexes in vivo reveals differential effects of covalent modifications on different Saccharomyces cerevisiae PP2A heterotrimers."  Eukaryotic Cell.  4 (6): 1029-1040.
    » Click here for download (465KB PDF).
14. Jeroen Dobbelaere, Matthew S. Gentry, Richard L. Hallberg, and Yves Barral.  "Phosphorylation-dependent regulation of septin dynamics during the cell cycle."  2003.  Developmental Cell.  4 (3): 345-57.
    » Click here for download (4.04MB PDF).
15. Matthew S. Gentry and Richard L. Hallberg.  2002.  "Localization of Saccharomyces cerevisiae protein phosphatase 2A subunits throughout the mitotic cell cycle."  Molecular Biology of the Cell. 13 (10): 3477-3492.
    » Click here for download (695KB PDF).