Matthew S Gentry

Matthew S Gentry,

Professor & Chair

Department: MD-BIOCHEM / MOLECULAR BIOL
Business Phone: (352) 294-8387
Business Email: matthew.gentry@ufl.edu

About Matthew S Gentry

Dr. Matthew S. Gentry is Professor & Chair of Biochemistry & Molecular Biology in the College of Medicine at University of Florida. He is a prominent brain metabolism scientist who has made seminal discoveries in the realm of brain glycogen and glucose metabolism and how perturbations in these pathways impact neuro-centric diseases. Dr. Gentry has nearly 20 years of experience working on glycogen storage diseases (GSD). He did research on cell signaling and cell division at Syracuse University for his Ph.D in Molecular Biology (2003) and then worked on the GSD and childhood dementia called Lafora disease as a postdoctoral scholar in the laboratory of Dr. Jack Dixon at UC-San Diego where he defined the biochemical properties of the genes mutated in the disease. Building on this foundational biochemistry, he has been continuously funded by NIH since 2007 via a K99/R00; multiple R01 grants; a P01; a recent R35 that focuses on Brain Glycogen – Metabolism, Mechanisms, and Therapeutic Potential; other NIH grants; and funding from foundations and industry. He has also been continuously funded by NSF since receiving a NSF CAREER award in 2013 to study the enzymology and structure/function of metabolic enzymes. His lab works on a number of CNS-centric GSDs and the role of glycogen in cancer, focusing on defining disease mechanisms, pre-clinical drugs and clinical biomarkers.

Additional Positions:
Professor & Chair
2022 – Current · University of Florida College of Medicine
Professor
2016 – 2022 · University of Kentucky College of Medicine
Associate Professor
2013 – 2016 · University of Kentucky College of Medicine
Assistant Professor
2008 – 2013 · University of Kentucky College of Medicine

Accomplishments

Exceptional Mentor Award
2021 · UK Office of Biomedical Education
Excellence in Medical Education Award for Mentoring
2020 · Academy of Medical Educator
Antonio S. Turco Endowed Professor in Biochemistry
2019-2022 · University of Kentucky
Story Landis Award for Outstanding Mentorship
2018 · NINDS
Outstanding Mentoring Award
2017 · UK Center for Clinical and Translational Research
University Research Professor
2017 · University of Kentucky
Editorial Board
2014-2024 · The Journal of Biological Chemistry
Thomas Maciag Award for excellence in scientific discoveries and mentoring
2014 · NIH IDeA
CAREER Award
2013-2018 · National Science Foundation (NSF)
Scientific Travel Award
2008 · American Society of Biochemistry and Molecular Biology (ASBMB)
K99 Pathway to Independence Award
2007 · NINDS/NIH
Post-Doctoral Training Grant
2004-2006 · NCI: Biochemistry of Growth Regulation and Oncogenesis

Research Profile

Dr. Gentry is Director of the NIH-funded Lafora Epilepsy Cure Initiative (LECI) and Chair of Biochemistry & Molecular Biology at University of Florida. The LECI is a consortium of Lafora disease (LD) researchers from around the world funded by a NIH P01 (PI: Gentry) to define the basic mechanisms of LD and translate the findings into pre-clinical therapies. LD is a glycogen storage disease, progressive myoclonic epilepsy, and childhood dementia. He has been working on LD for 17 years to define the disease-causing mechanisms of this fatal autosomal recessive disease and to develop therapies. This work has yielded three therapeutic platforms: traditional small molecule, anti-sense oligonucleotide, and an antibody-enzyme fusion. Each drug targets glycogen and either down-regulates glycogen metabolism or degrades aberrant glycogen-link accumulations. He is also PI of a non-overlapping NINDS R35 on brain metabolism and has been continuously funded by NIH since 2007. Collectively, the Sun and Gentry labs established a pipeline to perform traditional and spatial metabolomics on samples from control and diseased mice that yield foundational insights into both normal and diseased metabolic pathways. Collaborating with the Sun laboratory at UF, the Gentry laboratory studies: Alzheimer’s disease, Lafora disease, Glut1 Deficiency Syndrome, Pompe disease, Cori disease, traumatic brain injury, spinal cord injury, lung cancer, and Ewing sarcoma while collaborating with numerous other labs on exciting projects.

LD is caused by mutations in either the gene encoding for laforin or the gene encoding for malin that when mutated results in pathogenic polyglucosan bodies (PGBs). He discovered the activity of malin as an E3 ubiquitin ligase and laforin as a glycogen phosphatase, characterized their biochemical properties, determined the first crystal structures, developed assays to characterize their substrate specificities, defined their functions in vivo, established novel methodologies to assess PGBs, and developed an antibody-enzyme fusion (AEF) to degrade PGBs. Excitingly, the AEF ablates PGBs in vivo in LD mouse models in muscle, heart, and the brain. This AEF is a promising pre-clinical therapeutic for LD with the potential of being the first LD drug.

His laboratory’s work has been recognized by the scientific community via invitations for review articles, talks at national/international symposia, and requests to serve on grant review committees. Dr. Gentry has been recognized for outstanding mentoring with the 2014 NIH IDeA Maciag Award, the 2017 NIH CCTS mentoring award, the 2018 NINDS Story Landis award, and the 2020 Academy of Medical Educator Excellence in Medical Education Award for Mentorship.

Open Researcher and Contributor ID (ORCID)

0000-0001-5253-9049

Areas of Interest
  • Adult Polyglucosan Body Disease
  • Alzheimer’s Disease
  • Biomarkers
  • Brain metabolism
  • Cancer metabolism
  • Carbohydrate metabolism
  • Drug discovery
  • Ewing’s sarcoma
  • Glut1 Deficiency Syndrome
  • Glycogen Storage Diseases
  • Glycosylation
  • Lafora disease
  • MALDI Imaging
  • Mass Spectrometry
  • Neurodegenerative diseases
  • Pompe Disease
  • Toxoplasma gondii
  • lung adenocarcinoma

Publications

2022
Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer.
Cell death and differentiation. 29(10):1913-1927 [DOI] 10.1038/s41418-022-00974-5. [PMID] 35332310.
2022
Analysis of circulating metabolites to differentiate Parkinson’s disease and essential tremor.
Neuroscience letters. 769 [DOI] 10.1016/j.neulet.2021.136428. [PMID] 34971771.
2022
Differential activity of glucan phosphatase starch EXcess4 orthologs from agronomic crops
Biocatalysis and Agricultural Biotechnology. 45 [DOI] 10.1016/j.bcab.2022.102479.
2022
High-dimensionality reduction clustering of complex carbohydrates to study lung cancer metabolic heterogeneity.
Advances in cancer research. 154:227-251 [DOI] 10.1016/bs.acr.2022.02.005. [PMID] 35459471.
2022
In situ mass spectrometry imaging reveals heterogeneous glycogen stores in human normal and cancerous tissues.
EMBO molecular medicine. 14(11) [DOI] 10.15252/emmm.202216029. [PMID] 36059248.
2022
In situ spatial glycomic imaging of mouse and human Alzheimer’s disease brains.
Alzheimer's & dementia : the journal of the Alzheimer's Association. 18(10):1721-1735 [DOI] 10.1002/alz.12523. [PMID] 34908231.
2022
Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency.
Science translational medicine. 14(665) [DOI] 10.1126/scitranslmed.abn2956.
2022
The Toxoplasma glucan phosphatase TgLaforin utilizes a distinct functional mechanism that can be exploited by therapeutic inhibitors
Journal of Biological Chemistry. 298(7) [DOI] 10.1016/j.jbc.2022.102089. [PMID] 35640720.
2022
Tissue-Specific Downregulation of Fatty Acid Synthase Suppresses Intestinal Adenoma Formation via Coordinated Reprograming of Transcriptome and Metabolism in the Mouse Model of Apc-Driven Colorectal Cancer
International Journal of Molecular Sciences. 23(12) [DOI] 10.3390/ijms23126510. [PMID] 35742953.
2022
Two Diseases—One Preclinical Treatment Targeting Glycogen Synthesis
Neurotherapeutics. 19(3):977-981 [DOI] 10.1007/s13311-022-01240-9. [PMID] 35460010.
2021
An empirical pipeline for personalized diagnosis of Lafora disease mutations
iScience. 24(11) [DOI] 10.1016/j.isci.2021.103276. [PMID] 34755096.
2021
APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis.
Molecular neurodegeneration. 16(1) [DOI] 10.1186/s13024-021-00483-y. [PMID] 34488832.
2021
Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease.
Brain : a journal of neurology. 144(8):2349-2360 [DOI] 10.1093/brain/awab110. [PMID] 33822008.
2021
Brain glycogen serves as a critical glucosamine cache required for protein glycosylation.
Cell metabolism. 33(7):1404-1417.e9 [DOI] 10.1016/j.cmet.2021.05.003. [PMID] 34043942.
2021
Emerging roles of N-linked glycosylation in brain physiology and disorders.
Trends in endocrinology and metabolism: TEM. 32(12):980-993 [DOI] 10.1016/j.tem.2021.09.006. [PMID] 34756776.
2021
Generation and characterization of a laforin nanobody inhibitor
Clinical Biochemistry. 93:80-89 [DOI] 10.1016/j.clinbiochem.2021.03.017. [PMID] 33831386.
2021
Hippocampal disruptions of synaptic and astrocyte metabolism are primary events of early amyloid pathology in the 5xFAD mouse model of Alzheimer’s disease.
Cell death & disease. 12(11) [DOI] 10.1038/s41419-021-04237-y. [PMID] 34657143.
2021
Lactate supports a metabolic-epigenetic link in macrophage polarization
Science Advances. 7(46) [DOI] 10.1126/sciadv.abi8602. [PMID] 34767443.
2021
Serotonergic therapy in epilepsy.
Current opinion in neurology. 34(2):206-212 [DOI] 10.1097/WCO.0000000000000901. [PMID] 33664206.
2021
The 6th International Lafora Epilepsy Workshop: Advances in the search for a cure
Epilepsy & Behavior. 119 [DOI] 10.1016/j.yebeh.2021.107975. [PMID] 33946009.
2020
Accurate and sensitive quantitation of glucose and glucose phosphates derived from storage carbohydrates by mass spectrometry
Carbohydrate Polymers. 230 [DOI] 10.1016/j.carbpol.2019.115651. [PMID] 31887930.
2020
APOE alters glucose flux through central carbon pathways in astrocytes.
Neurobiology of disease. 136 [DOI] 10.1016/j.nbd.2020.104742. [PMID] 31931141.
2020
Clear Cell Adenocarcinoma of the Urinary Bladder Is a Glycogen-Rich Tumor with Poorer Prognosis
Journal of Clinical Medicine. 9(1) [DOI] 10.3390/jcm9010138. [PMID] 31947882.
2020
Frontotemporal dementia non-sense mutation of progranulin rescued by aminoglycosides.
Human molecular genetics. 29(4):624-634 [DOI] 10.1093/hmg/ddz280. [PMID] 31913476.
2020
Polyglucosan body structure in Lafora disease
Carbohydrate Polymers. 240 [DOI] 10.1016/j.carbpol.2020.116260. [PMID] 32475552.
2020
Spatial profiling of gangliosides in mouse brain by mass spectrometry imaging
Journal of Lipid Research. 61(12) [DOI] 10.1194/jlr.ilr120000870.
2020
The 5th International Lafora Epilepsy Workshop: Basic science elucidating therapeutic options and preparing for therapies in the clinic.
Epilepsy & behavior : E&B. 103(Pt A) [DOI] 10.1016/j.yebeh.2019.106839. [PMID] 31932179.
2020
The E3 ligase malin plays a pivotal role in promoting nuclear glycogenolysis and histone acetylation.
Annals of translational medicine. 8(5) [DOI] 10.21037/atm.2020.01.130. [PMID] 32309401.
2019
Antibody-Mediated Enzyme Therapeutics and Applications in Glycogen Storage Diseases
Trends in Molecular Medicine. 25(12):1094-1109 [DOI] 10.1016/j.molmed.2019.08.005. [PMID] 31522955.
2019
Brain Glycogen Structure and Its Associated Proteins: Past, Present and Future.
Advances in neurobiology. 23:17-81 [DOI] 10.1007/978-3-030-27480-1_2. [PMID] 31667805.
2019
Central Nervous System Delivery and Biodistribution Analysis of an Antibody–Enzyme Fusion for the Treatment of Lafora Disease
Molecular Pharmaceutics. 16(9):3791-3801 [DOI] 10.1021/acs.molpharmaceut.9b00396. [PMID] 31329461.
2019
Clinical Features, Survival and Prognostic Factors of Glycogen-Rich Clear Cell Carcinoma (GRCC) of the Breast in the U.S. Population.
Journal of clinical medicine. 8(2) [DOI] 10.3390/jcm8020246. [PMID] 30769905.
2019
Nuclear Glycogenolysis Modulates Histone Acetylation in Human Non-Small Cell Lung Cancers.
Cell metabolism. 30(5):903-916.e7 [DOI] 10.1016/j.cmet.2019.08.014. [PMID] 31523006.
2019
Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion.
Cell metabolism. 30(4):689-705.e6 [DOI] 10.1016/j.cmet.2019.07.002. [PMID] 31353261.
2019
The 4th International Lafora Epilepsy Workshop: Shifting paradigms, paths to treatment, and hope for patients
Epilepsy & Behavior. 90:284-286 [DOI] 10.1016/j.yebeh.2018.11.014. [PMID] 30528121.
2018
A novel EPM2A mutation yields a slow progression form of Lafora disease
Epilepsy Research. 145:169-177 [DOI] 10.1016/j.eplepsyres.2018.07.003. [PMID] 30041081.
2018
Lafora disease offers a unique window into neuronal glycogen metabolism.
The Journal of biological chemistry. 293(19):7117-7125 [DOI] 10.1074/jbc.R117.803064. [PMID] 29483193.
2018
Nucleoside triphosphate cosubstrates control the substrate profile and efficiency of aminoglycoside 3′-O-phosphotransferase type IIa.
MedChemComm. 9(8):1332-1339 [DOI] 10.1039/c8md00234g. [PMID] 30151088.
2018
Oligomerization and carbohydrate binding of glucan phosphatases
Analytical Biochemistry. 563:51-55 [DOI] 10.1016/j.ab.2018.10.003. [PMID] 30291838.
2018
The 3rd International Lafora Epilepsy Workshop: Evidence for a cure.
Epilepsy & behavior : E&B. 81:125-127 [DOI] 10.1016/j.yebeh.2017.12.015. [PMID] 29475602.
2018
The UBA domain of SnRK1 promotes activation and maintains catalytic activity.
Biochemical and biophysical research communications. 497(1):127-132 [DOI] 10.1016/j.bbrc.2018.02.039. [PMID] 29428737.
2018
The unique evolution of the carbohydrate-binding module CBM20 in laforin.
FEBS letters. 592(4):586-598 [DOI] 10.1002/1873-3468.12994. [PMID] 29389008.
2017
What’s in a name?
eLife. 6 [DOI] 10.7554/elife.32437.
2016
Assessing the Biological Activity of the Glucan Phosphatase Laforin.
Methods in molecular biology (Clifton, N.J.). 1447:107-19 [DOI] 10.1007/978-1-4939-3746-2_7. [PMID] 27514803.
2016
Erratum to: Unique carbohydrate binding platforms employed by the glucan phosphatases.
Cellular and molecular life sciences : CMLS. 73(14) [PMID] 27262704.
2016
Plant α-glucan phosphatases SEX4 and LSF2 display different affinity for amylopectin and amylose.
FEBS letters. 590(1):118-28 [DOI] 10.1002/1873-3468.12027. [PMID] 26763114.
2016
Reexamining Chronic Toxoplasma gondii Infection: Surprising Activity for a “Dormant” Parasite.
Current clinical microbiology reports. 3(4):175-185 [DOI] 10.1007/s40588-016-0045-3. [PMID] 28191447.
2016
Structural biology of glucan phosphatases from humans to plants
Current Opinion in Structural Biology. 40:62-69 [DOI] 10.1016/j.sbi.2016.07.015. [PMID] 27498086.
2016
Structural mechanisms of plant glucan phosphatases in starch metabolism.
The FEBS journal. 283(13):2427-47 [DOI] 10.1111/febs.13703. [PMID] 26934589.
2016
Unique carbohydrate binding platforms employed by the glucan phosphatases.
Cellular and molecular life sciences : CMLS. 73(14):2765-2778 [DOI] 10.1007/s00018-016-2249-3. [PMID] 27147465.
2015
Mechanistic Insights into Glucan Phosphatase Activity against Polyglucan Substrates.
The Journal of biological chemistry. 290(38):23361-70 [DOI] 10.1074/jbc.M115.658203. [PMID] 26231210.
2015
Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease.
Molecular cell. 57(2):261-72 [DOI] 10.1016/j.molcel.2014.11.020. [PMID] 25544560.
2014
Expression, purification and characterization of soluble red rooster laforin as a fusion protein in Escherichia coli.
BMC biochemistry. 15 [DOI] 10.1186/1471-2091-15-8. [PMID] 24690255.
2014
HUWE1 is a molecular link controlling RAF-1 activity supported by the Shoc2 scaffold.
Molecular and cellular biology. 34(19):3579-93 [DOI] 10.1128/MCB.00811-14. [PMID] 25022756.
2014
Phosphoglucan-bound structure of starch phosphatase Starch Excess4 reveals the mechanism for C6 specificity.
Proceedings of the National Academy of Sciences of the United States of America. 111(20):7272-7 [DOI] 10.1073/pnas.1400757111. [PMID] 24799671.
2013
A bioassay for Lafora disease and laforin glucan phosphatase activity.
Clinical biochemistry. 46(18):1869-76 [DOI] 10.1016/j.clinbiochem.2013.08.016. [PMID] 24012855.
2013
A malachite green-based assay to assess glucan phosphatase activity.
Analytical biochemistry. 435(1):54-6 [DOI] 10.1016/j.ab.2012.10.044. [PMID] 23201267.
2013
Dimerization of the glucan phosphatase laforin requires the participation of cysteine 329.
PloS one. 8(7) [DOI] 10.1371/journal.pone.0069523. [PMID] 23922729.
2013
Laforin, a protein with many faces: glucan phosphatase, adapter protein, et alii.
The FEBS journal. 280(2):525-37 [DOI] 10.1111/j.1742-4658.2012.08549.x. [PMID] 22364389.
2013
Structure of the Arabidopsis glucan phosphatase like sex four2 reveals a unique mechanism for starch dephosphorylation.
The Plant cell. 25(6):2302-14 [DOI] 10.1105/tpc.113.112706. [PMID] 23832589.
2012
Deciphering the role of malin in the lafora progressive myoclonus epilepsy.
IUBMB life. 64(10):801-8 [DOI] 10.1002/iub.1072. [PMID] 22815132.
2012
Laforin and malin knockout mice have normal glucose disposal and insulin sensitivity.
Human molecular genetics. 21(7):1604-10 [DOI] 10.1093/hmg/ddr598. [PMID] 22186021.
2011
Lafora disease E3-ubiquitin ligase malin is related to TRIM32 at both the phylogenetic and functional level.
BMC evolutionary biology. 11 [DOI] 10.1186/1471-2148-11-225. [PMID] 21798009.
2011
Laforin, a dual specificity phosphatase involved in Lafora disease, is present mainly as monomeric form with full phosphatase activity.
PloS one. 6(8) [DOI] 10.1371/journal.pone.0024040. [PMID] 21887368.
2011
Laforin, a dual-specificity phosphatase involved in Lafora disease, is phosphorylated at Ser25 by AMP-activated protein kinase.
The Biochemical journal. 439(2):265-75 [DOI] 10.1042/BJ20110150. [PMID] 21728993.
2011
The phosphoglucan phosphatase like sex Four2 dephosphorylates starch at the C3-position in Arabidopsis.
The Plant cell. 23(11):4096-111 [DOI] 10.1105/tpc.111.092155. [PMID] 22100529.
2010
Adenovirus protein E4orf4 induces premature APCCdc20 activation in Saccharomyces cerevisiae by a protein phosphatase 2A-dependent mechanism.
Journal of virology. 84(9):4798-809 [DOI] 10.1128/JVI.02434-09. [PMID] 20164229.
2010
Structural basis for the glucan phosphatase activity of Starch Excess4.
Proceedings of the National Academy of Sciences of the United States of America. 107(35):15379-84 [DOI] 10.1073/pnas.1009386107. [PMID] 20679247.
2009
Conservation of the glucan phosphatase laforin is linked to rates of molecular evolution and the glucan metabolism of the organism.
BMC evolutionary biology. 9 [DOI] 10.1186/1471-2148-9-138. [PMID] 19545434.
2009
Lafora disease: insights into neurodegeneration from plant metabolism.
Trends in biochemical sciences. 34(12):628-39 [DOI] 10.1016/j.tibs.2009.08.002. [PMID] 19818631.
2009
STARCH-EXCESS4 is a laforin-like Phosphoglucan phosphatase required for starch degradation in Arabidopsis thaliana.
The Plant cell. 21(1):334-46 [DOI] 10.1105/tpc.108.064360. [PMID] 19141707.
2009
Structural insights into glucan phosphatase dynamics using amide hydrogen-deuterium exchange mass spectrometry.
Biochemistry. 48(41):9891-902 [DOI] 10.1021/bi9008853. [PMID] 19754155.
2008
Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG).
The Journal of biological chemistry. 283(7):4069-76 [PMID] 18070875.
2007
A conserved phosphatase cascade that regulates nuclear membrane biogenesis.
Proceedings of the National Academy of Sciences of the United States of America. 104(16):6596-601 [PMID] 17420445.
2007
A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori’s disease.
Genes & development. 21(19):2399-409 [PMID] 17908927.
2007
An in vivo assay to quantify stable protein phosphatase 2A (PP2A) heterotrimeric species.
Methods in molecular biology (Clifton, N.J.). 365:71-83 [PMID] 17200555.
2007
The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease.
The Journal of cell biology. 178(3):477-88 [PMID] 17646401.
2006
Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates.
The Journal of biological chemistry. 281(41):30412-8 [PMID] 16901901.
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):1029-40 [PMID] 15947195.
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 of the United States of America. 102(24):8501-6 [PMID] 15930137.
2003
Phosphorylation-dependent regulation of septin dynamics during the cell cycle.
Developmental cell. 4(3):345-57 [PMID] 12636916.
2002
Localization of Saccharomyces cerevisiae protein phosphatase 2A subunits throughout mitotic cell cycle.
Molecular biology of the cell. 13(10):3477-92 [PMID] 12388751.
2000
Loss of a protein phosphatase 2A regulatory subunit (Cdc55p) elicits improper regulation of Swe1p degradation.
Molecular and cellular biology. 20(21):8143-56 [PMID] 11027284.
APOE4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis
. [DOI] 10.1101/2020.10.19.345991.
Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion
. [DOI] 10.1101/679407.

Education

Postdoctoral Scholar
2003-2008 · UC-San Diego
Ph.D. in Molecular Biology
2003 · Syracuse University
B.S. in Biology
1996 · University of Evansville

Contact Details

Phones:
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Emails:
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Addresses:
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