Investigation of Neural Pathogenic Mechanisms Associated with Congenital Disorders of Glycosylation

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

Program Summary This Program Project grant will use multiple model systems and approaches to address the pathogenic mechanisms associated with neural disease in the Congenital Disorders of Glycosylation (CDG), with the long- term goals of elucidating how glycosylation regulates neural function. Nearly all identified CDG types have neurological involvement, but the molecular and cellular basis for these phenotypes is poorly understood. This limited understanding of the pathogenic mechanisms has greatly impeded therapy development. The overall Program is organized into three Research Projects, a Research Core, and an Administrative Core. The three Research Projects will utilize zebrafish, Drosophila and human neural models, with each model system bringing distinct advantages to the Program. The overall Program is structured to allow mechanisms identified in one Project to be investigated and further elaborated in the other systems, and to permit the collective and diverse expertise of the team to be actively shared across projects. Our combined and integrated expertise will create a Program with far greater impact than any of the individual Projects alone. We will focus on multiple CDG (PMM2-CDG, PIGA-CDG, ALG13-CDG), caused by pathogenic variants in the early steps of related biosynthetic pathways, with devastating neurologic phenotypes. These disorders of N-linked and glycosylphosphatidylinositol (GPI)-anchored glycosylation share many neurological phenotypes including ataxia, intellectual disability, and seizures. How defects in these two distinct glycosylation pathways converge to cause these common phenotypes is a major question addressed by this P01. Research Project 1 will leverage zebrafish models for PMM2-CDG and PIGA-CDG to define how defects in protein glycosylation and sugar phosphate metabolism impact neurons and glia during cerebellar development. Research Project 2 utilizes Drosophila to determine the cell-type and mutation-specific contributions to neurological disease in PIGA-CDG and PMM2-CDG, and to identify genetic modifiers of both disorders. Research Project 3 will utilize PMM2-CDG and ALG13-CDG human cortical organoids to investigate specific hypotheses on how altered glycosylation and metabolism impact neuronal excitability and network activity. The Research and Administrative Cores will provide key proteomic/glycoproteomic support, and scientific, logistical and fiscal oversight, respectively for all three Research Projects. This P01 brings together the demonstrated expertise of seven investigators at five different institutions, and is led by two PD/PIs with demonstrated leadership ability and clinical/basic science research expertise in CDG. The specific aims of the Overall Program, which represent the key scientific directions of the P01 are: 1) to investigate the specific cell types (neuron vs. glia) that drive CDG neural phenotypes, 2) to define the molecular basis of disease-associated neurological phenotypes, and identify the sensitive glycoproteins and pathways responsible for these phenotypes, and 3) to perform functional analyses of identified genetic modifiers of CDG disease pathogenesis.