Role of DYT6 Dystonia Protein THAP1 in Oligodendroglial Mediated ECM Homeostasis During CNS Development

Abstract / Project Summary The brain extracellular matrix (ECM) is a complex three-dimensional milieu that has a profound influence on synaptic plasticity and myelination during development. Previous work has established that differentiation of the oligodendrocyte progenitor cells (OPCs) into mature myelinating oligodendrocytes (OLs) is strongly influenced by the ECM composition. The long-term goals of this project are to understand the mechanisms by which glia and ECM contribute to CNS motor function including defining how disruption of these processes contribute to pathogenesis of dystonia and other neurodevelopmental disorders. The parent grant investigates the DYT6 dystonia gene, THAP1 in the glial lineage and the mechanisms by which they regulate ECM homeostasis. However, to understand the mechanism(s) of disruption of ECM homeostasis by the OPCs (an overarching goal of Aim 2) and how it mediates myelination and motor function (a central goal of Aim 3), we sought to generate and utilize new genetic tools that can directly manipulate ECM metabolism. The investigations proposed in the supplement will assess for myelination and motor function from the conditional loss of the THAP1-target gene Gusb, encoding β-glucuronidase, a lysosomal enzyme responsible for degrading glycosaminoglycan (GAG), mucopolysaccharide sugars that are major components of the ECM. In preliminary studies we have identified that global loss of Gusb results in hypomyelination. The proposed studies in this supplement will (Aim 1) Investigate the cell autonomous role of GAG catabolism in CNS myelination by generating novel mouse lines with conditional Gusb deletion in oligodendrocyte lineage (Olig2-Cre). We will then (Aim 2) Investigate the cellular mechanism of GAG catabolism on oligodendrocyte development using in vitro cultures of differentiating OPCs derived from mice with conditional deletion of Gusb and (Aim 3) Investigate the contribution of oligodendrocyte regulated GAG catabolism in motor learning using accelerating rotarod. Through this work, the supplement seeks to support and train Keenan Hope, a promising student pursuing his doctoral work in the department of Neurosciences at Case Western Reserve University. The supplement will support the graduate training and career development of Keenan Hope, who blongs to an underrepresented population in biomedical research and enhance the overall scientific approach of the parent grant.