Dystroglycanopathies are a group of congenital muscular dystrophies that involve brain malformations and severe mental retardation. Most of the identified causes are mutations in glycosyltransferases that cause hypoglycosylation of a-dystroglycan, an extracellular matrix receptor. The brain malformations, including type II lissencephaly are characterized as a type of neuronal migration disorder, for which no effective therapy exists. The long-term goal of this project is to develop gene therapeutic strategies to improve brain function. Surprisingly while abnormal brain architecture is believed to be the most critical contributor to the neural dysfunction and disorders, our recent studies provide compelling evidence that a number of key neural functions depend more critically on ongoing glycosylation in the adult brain. In particular we have found that spatial learning insufficiency is mainly cause by altered dendritic spine plasticity due to defective cell-ECM interactions and that restoration o glycosylation restores spine plasticity and improves brain function despite abnormal histological structures. Therefore, our Hypothesis is that postnatal gene therapy restores spine plasticity and improves brain function despite the malformed brain. This proposal focuses on the mechanisms of spatial learning deficits and its rescue by gene therapy as a first step to improve mental function in dystroglycanopathies.
The specific aims are designed to understand the mechanisms of spatial learning deficits and functional recovery by gene therapy.
Aim 1 : Determine the mechanisms of defective dendritic spine plasticity that contributes to spatial learning deficits in mouse models of dystroglycanopathies.
Aim 2 : Determine whether restoration of a-dystroglycan glycosylation by gene therapy rescues spatial learning in dystroglycanopathies despite the presence of brain malformations. This proposal will study the basis of spatial learning deficits and their correction via gene therapy without correcting the migration disorder itself using histological, electrophysiological, biochemical, and state-of-the-art genetic approaches. It will lead to improved understanding of the diseases and is expected to produce experimental therapies. The strategy of gene therapy targeted towards postnatal plasticity defects as opposed to correcting developmental histological defects may be broadly useful for other neuronal migration disorders.

Public Health Relevance

Congenital muscular dystrophies with central nervous system involvement are devastating diseases with no effective therapy. This project aims to study the mechanisms of brain dysfunction and develop an experimental gene therapy by using adeno-associated serotype 9 viral vectors to improve brain function.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Krotoski, Danuta
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Upstate Medical University
Other Basic Sciences
Schools of Medicine
United States
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