# GLT-1/EAAT2 signaling as a novel player in myelin repair

> **NIH NIH R21** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $426,938

## Abstract

Multiple Sclerosis (MS) is a progressive inflammatory demyelinating disease that affects the central nervous
system (CNS), and it is considered the most common non-traumatic debilitating neurologic disease in young
adults. Based on recent advances in the understanding of the disease mechanisms underlying MS, it has
become evident that clinical relapse and progressive accumulation of disability are driven by different
pathological processes. Importantly, current therapies for MS mostly target the chronic inflammatory component
mediating clinical relapse, and they are effective in modifying the disease course and in managing symptoms.
Relapse-independent disease progression, on the other hand, is to a large extent driven by the degeneration of
chronically demyelinated and hence more vulnerable axons. Hence, myelin restoration has 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
human brain, and therapeutic agents that limit progressive disease mechanisms and promote CNS repair
remain an important unmet challenge in MS clinical practice. 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, we
propose here to explore the role of a novel glutamate-driven signaling pathway that is initiated in maturing
oligodendrocytes (OLGs), the myelinating cells of the central nervous system (CNS), through activation of the
sodium-dependent glutamate transporter GLT-1, also known as excitatory amino acid transporter 2 (EAAT2) or
solute carrier family 1 member 2 (SLC1A2). In MS, and particularly in progressive MS, there is evidence that
this pathway is impaired, thereby limiting efficient myelin repair. Importantly, our preliminary data provide
compelling evidence that loss of GLT-1 in maturing OLGs limits myelin repair in the cuprizone model that reflects
features of particularly progressive stages of MS. In light of the glutamate homeostasis regulating role of GLT-1
in astrocytes, characterizing mechanisms downstream of GLT-1 activation in maturing OLGs represents a
critical step toward the identification of potential therapeutic targets. In this context, our preliminary data point
toward a critical role of the small GTPase RhoB and its unique functional roles in regulating endosomal and
myelin protein trafficking mechanisms. By characterizing the role of a promising new signaling cascade and
by investigating a molecular mechanism targeting more mature OLGs rather than OLG progenitor cells, our
studies address major gaps in the field. Notably, there is increasing evidence for an involvement of Rho
GTPase signaling and protein targeting in CNS myelin repair, and Rho GTPases emerge as promising
therapeutic targets. Thus, in the long-term, the proposed studies are anticipated to provide nov...

## Key facts

- **NIH application ID:** 10989063
- **Project number:** 1R21NS135262-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** BABETTE FUSS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $426,938
- **Award type:** 1
- **Project period:** 2024-07-09 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10989063

## Citation

> US National Institutes of Health, RePORTER application 10989063, GLT-1/EAAT2 signaling as a novel player in myelin repair (1R21NS135262-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10989063. Licensed CC0.

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