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Faculty Detail Faculty Entry   
Name MATHIEU JEAN LESORT  
Campus Address SC 1017 Zip 0017
Phone 205-934-2442
E-mail mlesort@uab.edu" id="FacultyDetail1EmailAddress"><a href="mailto:mlesort@uab.edu">mlesort@uab.edu</a>
URL
 
 

Department Affiliations(s)
Appointment Type Department Division Rank
Center  Neurology   Alzheimer's Disease Center Associate Professor
Center  General Clinical Research Center  Comprehensive Neuroscience Center Associate Professor
Center  General Clinical Research Center  Minority Health & Research Center Associate Professor
Center  Neurology   Neuro-Oncology Center Associate Professor
Primary  Psychiatry   Psych - Behavioral Neurobiology Associate Professor
Secondary  Cell Biology   Cell Biology Assistant Professor
Secondary  Pharmacology/Toxicology   Pharmacology/Toxicology Chair's Office Assistant Professor

Biographical Sketch 
1997 Ph.D., Neurobiology, Universite Pierre & Marie Curie, Paris, France
1997-2000 Postdoctoral Fellow, Department of Psychiatry and Behavioral Neurobiology,University of Alabama at Birmingham
2000-2001 Research Assistant Professor, Department of Psychiatry, UAB
2001-2010 Assistant Professor, Department of Psychiatry, UAB
Secondary, Department of Cell Biology, and Department of Pharmacology & Toxicology, UAB.
2004-present Associate Scientist, Minority Health & Research Center, UAB.
2006-present Faculty Member, Comprehensive Neuroscience Center, UAB.
2007-present Faculty Member, Neurodegeneration and Experimental Therapeutics Center, UAB.
2008-present Associate Scientist, Alzheimer’s Disease Research Center, UAB.
2009-present Member of the Genetics and Genomic Sciences Graduate Program Faculty, UAB.
2009-present Member of the Cell, Molecular and Developmental Biology Graduate Program Faculty, UAB.
2010-present Associate Professor, Department of Psychiatry, UAB

Society Memberships
Organization Name Position Held Org Link
No records
 

Research/Clinical Interest
Title
Pathogenesis of Huntington’s Disease: from models to therapeutic targets
Description
Neurodegeneration is a common issue in many nervous system diseases such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease. These diseases are devastating and expensive, with a huge direct and indirect societal cost of care. Although substantial progresses have been made over the past few years, the pathogenesis of these neurodegenerative diseases have not been identified in sufficient detail to suggest corrective interventions other than symptomatic treatments. As a neurobiologist my research interest is directed toward understanding the pathophysiology of neurodegenerative diseases, in order to propose therapeutic strategies that will delay the onset or slow the progression of these diseases. More specifically, the past and present focus of my research group is dealing with the molecular mechanisms that contribute to the pathogenic processes of Huntington’s disease, Alzheimer’s disease and more recently in Parkinson’s disease. To expand our knowledge and identify potential novel therapeutic targets we have adopted a multidisciplinary approach that takes advantage of a wide variety of in vitro, cell culture and whole animal models. These models faithfully recapitulate specific characteristics of neurodegenerative diseases and constitute the basis to elucidate the pathogenic mechanisms involved in disease processes and to evaluate the relevance of our findings from an in vitro setting to an in vivo situation.

Alzheimer’s Disease Study
Recent studies have found close relationships between Alzheimer’s disease and diabetes. Diabetes occurs when the hormone insulin becomes unable to perform one of its most important functions—regulating the body’s use of glucose (sugar). This condition, also called insulin resistance, can lead to impaired brain function. In fact, studies suggest that diabetics have almost twice as great a risk of acquiring Alzheimer’s as do non-diabetics. Yet the exact links between insulin resistance and brain disorders have not been fully identified. One of the ongoing projects of my research group is to identify the mechanistic links and influential mechanisms by which diabetes promotes AD.

Huntington’s Disease Study
A primary interest of my research group is directed toward understanding the specific mechanisms by which the mutated huntingtin protein initiates the pathogenesis of Huntington’s disease in order to identify potential targets for therapeutic approaches. Huntington’s disease is a devastating inherited neurodegenerative disorder caused by an unstable expanded CAG trinucleotide repeat within the coding sequence of the huntingtin gene resulting in an abnormally expanded polyglutamine stretch at the protein level. Despite the finding of the disease-causing mutation, the precise mechanisms leading to the neurodegeneration in HD remain uncertain. Potential mechanisms include those that distinguish wild type and mutant huntingtin properties. For instance, it has been proposed that HD could be caused in part by abnormal protein-protein interactions related to the elongated polyglutamine stretch in the mutated huntingtin. Our HD research program focuses on three topics: role of transglutaminase, proteolysis and cleavage of huntingtin, and mitochondria dysfunction.

Parkinson’s Disease
A very recent ongoing project of my research group proposes to inhibit the mitochondrial permeability transition induction as a potential means of attenuating Parkinson’s disease-related neurodegeneration.

Postdoc Positions Available
Date Posted Position Title
No records
 

Selected Publications 
Publication PUBMEDID
Lesort M*., Lee M., Tucholski J., Johnson G.V.W. 2003 Cystamine inhibits caspase activity: implication for polyglutamine disorders. Journal of Biological Chemistry 278:3825-3830. * Corresponding author.

Ruan, Q., Lesort, M., MacDonald, M. E., and Johnson, G. V., 2004, Striatal cells from mutant huntingtinknock-in mice are selectively vulnerable to mitochondrial complex II inhibitor-induced cell death through a non-apoptotic pathway, Human Molecular Genetics 13:669-681.

Choo Y., Johnson G. V., MacDonald M., Detloff P. J., and Lesort M., 2004, Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome C release. Human Molecular Genetic 13:1407-20.

Hunter J.M., Crouse A.B., Lesort M., Johnson G.V.W., Detloff. P.J. 2005. Verification of Somatic CAG Repeat Expansion by Pre-PCR Fractionation. Journal of Neuroscience Methods, May 15;144:11-17.

Choo YS, Mao Z, Johnson GV, Lesort M. 2005. Increased glutathione levels in cortical and striatal mitochondria of the R6/2 Huntington's disease mouse model. Neuroscience Letters.386:63-68.

Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM, Myers RH, Lesort M, Macdonald ME. 2005. HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Human Molecular Genetics.14:2871-2880.

Mao Z, Choo YS, Lesort M 2006. Cystamine and Cysteamine Prevent the 3-NP-Induced Mitochondrial Depolarization of Huntington’s Disease Knock-in Striatal Cells. 2006. European Journal of Neuroscience 23, 1701-1710.

Hunter JM, Lesort M1 and Johnson GVW1. 2007. Ubiquitin-proteasome system alterations in a striatal cell model of Huntington's disease. 2007. Journal of Neuroscience Research 85, 1774-1788. 1 These authors contributed equally to this work.

Perry G, Tallaksen-Greene S, Kumar A, Heng MY, Kneynsberg A, van Groen T, Detloff P, Albin R and Lesort M. Mitochondrial calcium uptake capacity as a therapeutic target in the R6/2 mouse model of Huntington’s disease. Human Molecular Genetics (2010) 19 (17): 3354-3371. PMID: 20558522.

Reyes RC, Perry G, Lesort M, Parpura V. (2010) Immunophilin deficiency augments Ca(2+) dependent glutamate release from mouse cortical astrocytes. Cell Calcium. Dec 14.


Mary Y. Heng, Duy K. Duong, *Roger L. Albin, Sara J. Tallaksen-Greene, Jesse M. Hunter, Mathieu J. Lesort, Alex Osmand, Henry L. Paulson1, Peter J. Detloff. 2010 Early Autophagic Response in a Novel Knock-In Model of Huntington Disease. Human Molecular Genetics. Hum. Mol. Genet. (2010) 19 (19): 3702-3720.

Tower C, Fu L, Prichard M, Lesort M and Sztul E. Human Cytomegalovirus UL97 Kinase Prevents the Deposition of Mutant Proteins in Cellular Models of Huntington's Disease and Ataxia. Neurobiology of Disease 2011 Jan;41(1):11-22. doi:10.1016/j.nbd.2010.08.013.

Adrienne L. King, Telisha M. Swain, Mathieu J. Lesort, Dale A. Dickinson and Shannon M. Bailey. Chronic ethanol consumption enhances sensitivity to Ca2+-mediated opening of the mitochondrial permeability transition pore and increases cyclophilin D levels in liver. American Journal of Pathology Am J Physiol Gastrointest Liver Physiol. 2010 Oct;299(4):G954-66.

Sunny R. Slone, Mathieu Lesort, and Talene A. Yacoubian. 14-3-3theta Protects Against Neurotoxicity in a Cellular Parkinson’s Disease Model Through Inhibition of the Apoptotic Factor Bax. PLoS One. 2011;6(7):e21720.

Dougherty SE, Reeves JL, Lucas EK, Gamble KL, Lesort M, Cowell RM. (2012) Disruption of Purkinje cell function prior to huntingtin accumulation and cell loss in an animal model of Huntington Disease. Exp Neurol. 2012 Jul;236(1):171-8. Epub 2012 May 2.

Kumar A, Kneynsberg A, Tucholski J, Perry G, van Groen T, Detloff PJ, Lesort M. (2012) Tissue transglutaminase overexpression does not modify the disease phenotype of the R6/2 mouse model of Huntington's disease. Experimental Neurology (In Press).

 		  
 

Keywords
Huntington Alzheimer Neurodegenerative Diseases

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