GLT-1/EAAT2: A Novel Player in Myelin Repair
Abstract
Multiple Sclerosis (MS), the most common inflammatory demyelinating disorder in humans, is characterized by a chronic, progressive disease course that ultimately leads to permanent neurologic disability caused, to a large extent, by the degeneration of chronically demyelinated and hence more vulnerable axons. Myelin restoration has, therefore, emerged as a promising strategy toward a regenerative treatment for MS. At present, however, we are only at the very beginning of developing practical approaches with the potential to promote myelin regeneration in vivo in the brain, and clinical translation has lagged expectation. Thus, there is a critical need to broaden the scope of druggable targets to advance the design of myelin regenerating therapies for MS. To address this need, our studies proposed here will explore a novel molecular mechanism that is involved in the modulation of myelin formation. More specifically, our preliminary findings point toward a critical contribution of a cell membrane integral protein named GLT-1, also known as excitatory amino acid transporter 2 (EAAT2) or solute carrier family 1 member 2 (SLC1A2), to the mechanisms regulating myelination. In this role, GLT-1 is present on maturing oligodendrocytes (OLGs), the myelinating cells of the central nervous system (CNS), and activated by the excitatory amino acid glutamate; in this scenario, glutamate is released by axons to promote myelin formation via activation of GLT-1. Importantly, there is good evidence for dysfunction of this glutamate-GLT-mediated mechanism in, particularly, progressive MS, leading to impairment of myelin repair and chronic demyelination of axons. Hence, investigating the contribution of this mechanism to myelin repair in animal models of inflammatory demyelination, as proposed here, directly addresses the Focus Area Central Nervous System Regenerative Potential in Demyelinating Conditions. In the short term, the proposed experiments will provide critical new insight into the role of glutamate-GLT-1-mediated events in maturing OLGs during CNS myelin repair within the context of diverse inflammatory environments. The overall topic of this study is considered timely and of high potential impact to the field since it addresses major gaps in knowledge by, first, characterizing a novel molecular mechanism regulating CNS remyelination and, second, investigating a mechanism that is targeting more mature OLG stages that have only recently been recognized as potential major players in myelin repair. Thus, defining dysfunctions in glutamate-GLT-1 mediated mechanisms in maturing OLGs as critical contributors to the barriers in myelin repair represents an important advancement toward a better understanding on how to stimulate myelin repair and regeneration. Importantly, the data to be gained from the proposed studies will provide the foundation for more mechanistic studies in which to further define the glutamate-GLT-1-initiated mechanisms in maturing OLGs and to, thereby, identify candidate molecular players that are preferentially acting in OLGs and may be targeted in a therapeutic approach designed to enhance myelin repair. Hence, in the long term, the proposed studies are anticipated to lead to a better understanding of the regulation of myelin repair in the CNS and to the characterization of novel therapeutic targets for stimulating CNS repair in MS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210842
Entities
People
- Babette Fuss
Organizations
- United States Army
- Virginia Commonwealth University