MeCP2 duplication syndrome is a severe and progressive neurological disorder caused by the duplication (or triplication) of the MeCP2 gene located on the X-chromosome. The disorder is characterized by intellectual disability, motor deficits, ataxia, epilepsy and premature death. Little is known about the molecular mechanisms underlying MeCP2 duplication syndrome and there is no treatment. We are studying this disorder using a transgenic mouse line, MeCP2-Tg, in which human MeCP2 gene locus is inserted on the X- chromosome and in which MeCP2 is expressed at 3 ? 5 times the normal level. As in humans, male but not female MeCP2-Tg mice display cognitive impairment, seizures, motor deficits, ataxia and die at 18 ? 20 weeks of age. We find that male MeCP2-Tg mice display highly elevated expression of glial fibrillary acidic protein (GFAP) and the microtubule-associated protein, Tau, in the hippocampus and cortex, but not appreciably in other brain parts. We propose that MeCP2 duplication syndrome is a neurodegenerative disorder that is triggered by elevated GFAP in astrocytes of the cortex and hippocampus leading to their dysfunction. A consequence of this is the elevation of extracellular glutamate, which increases Tau levels in neurons and promotes their death as a result of excitotoxicity. The goal of our proposal is to investigate the contributions of GFAP and Tau to the motor and cognitive deficits in MeCP2-Tg mice. This will be accomplished using cell culture models and MeCP2-Tg mice deficient in either GFAP or Tau. The specific goals of our proposal are: (1) To understand the mechanisms underlying selective neuronal vulnerability in MeCP2-Tg mice, (2) To investigate why MeCP2 duplication syndrome selectively affects males, and (3)To investigate the contribution of increased GFAP and Tau expression to neuronal death and behavioral deficits. Our research will provide a mechanistic framework for the understanding of the molecular and cellular underpinnings of MeCP2 duplication syndrome and will likely identify two proteins, the deregulation of which likely plays a key role in disease pathogenesis. If our hypothesis is correct, therapeutic approaches to lower GFAP and Tau levels will have benefit to patients with MeCP2 duplication syndrome.

Public Health Relevance

MeCP2 duplication or triplication syndrome is a rare but fatal neurological disorder caused by the duplication or triplication of the gene encoding Methyl-CpG-binding protein 2 (MeCP2). Little is known about molecular and cellular mechanisms underlying this disorder. We propose to conduct studies that will shed insight into the mechanisms underlying MeCP2 duplication / triplication syndrome using a combination of a cell culture model and a transgenic mouse model which recapitulates the neurological phenotype of patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS104508-02
Application #
9692819
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Mamounas, Laura
Project Start
2018-05-01
Project End
2019-05-21
Budget Start
2019-05-01
Budget End
2019-05-21
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Southern Methodist University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001981133
City
Dallas
State
TX
Country
United States
Zip Code
75275