Clinicians

Research Interests: We use model systems (primary cells, iPSCs, mouse) of rare genetic neurodevelopmental disorders that disrupt glycosylation (known as Congenital Disorders of Glycosylation, or CDG) and glycoproteomics to study glycosylation in the brain.

Research Details: Glycosylation is the enzyme-mediated process by which a carbohydrate (or “glycan”) is covalently attached to a target macromolecule (typically a protein or lipid). As the most abundant post-translational modification, glycosylation generates immense biological variability and mediates fundamental biological processes. The biological significance of glycosylation is emphasized by the Congenital Disorders of Glycosylation (CDG), a group of ~170 rare genetic diseases that disrupt glycosylation. CDG patients exhibit multiorgan dysfunction, including neurological deficits such as epilepsy and neurodevelopmental abnormalities. The pathophysiology of CDG is attributed to disrupted protein glycosylation. However, the specific identities of the hypoglycosylated proteins responsible for most disease manifestations are unknown. In the nervous system, key proteins involved in neurotransmitter release, neuronal cell signaling, and cellular migration events are glycosylated, yet our understanding of the role of glycosylation in these processes is rudimentary. The genetic basis of CDG provides an opportunity to identify the neurobiological functions of glycosylation using model systems and glycoproteomics. Disruptions in glycosylation have also been implicated in the pathophysiology of complex neurologic and psychiatric diseases, including Alzheimer disease, amyotrophic lateral sclerosis (AML), and schizophrenia. The goal of my lab is to elucidate the biological roles of glycosylation in the brain and to develop novel therapeutic approaches to treating glycosylation-related disease manifestations. We currently focus on two major types of glycosylation, N-linked and O-linked.

N-linked glycosylation: Most CDG disrupt N-glycosylation. The single most common genetic cause of CDG results from biallelic mutations in PMM2. Patients with PMM2-CDG typically suffer from multi-systemic symptoms, including prominent and progressive neurological symptoms, such as intellectual disability, seizures, and cerebellar hypoplasia with resulting ataxia. Lifelong neurological impairment is the largest source of morbidity for PMM2-CDG patients. Currently, there is no effective treatment. We have several mouse models that recapitulate various aspects of the disease. Currently, we are employing mass spectrometry-based approaches to identify disrupted glycosylation for identification and validation of the molecular pathophysiology of disease mechanisms.

O-linked glycosylation: Our lab recently identified a new genetic cause of CDG, caused by biallelic mutations in GALNT2, which encodes a Golgi-localized glycosyltransferase that initiates mucin-type O-glycosylation. Patients with GALNT2-CDG exhibit global developmental delay, multi-focal treatment-resistant epilepsy, autistic features, and white matter changes on brain MRI. Currently, there is no effective treatment. We developed a mouse model for this disorder, with mice exhibiting spontaneous seizures and deficits across numerous behavioral and learning domains. Time-locked video EEG recordings identify seizures in the majority of these mice, which increase in prevalence as the mice age. Genetic dissection of the circuit suggests that molecular events in both excitatory and inhibitory neurons contribute to development of spontaneous seizures. These findings implicate a role of O-glycosylation in diverse neurological processes, including learning, memory, and neurotransmission. Glycoproteomic analysis of brains from these mice identified candidate glycoproteins and disrupted O-glycosites that likely underlie these abnormalities.