Project Details
Projekt
Role of glutamate receptor-mediated Ca2+ signaling in regulating the fate of oligodendrocyte progenitors in multiple sclerosis
Applicant
Amit Agarwal, Ph.D.
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
from 2019 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 262890264
Multiple Sclerosis (MS) is assumed to be an autoimmune-mediated neuroinflammatory disease. In MS lesions, demyelinated axons exhibit decreased adenosine triphosphate (ATP) production and increased energy demand for action potential propagation, which lead to a state of “virtual hypoxia”. This chronic state of hypoxia initiates a sequela of events similar to those induced during ischemic conditions seen in stroke, such as glutamate and Ca2+ mediated toxicity, and disruption of mitochondrial function. Oligodendrocyte (OLs) precursor cells (OPCs), the progenitors that are involved in myelin repair, are abundant near regions of extensive demyelination. However, OPCs fail to respond appropriately suggesting that identifying pathways that inhibit or promote their differentiation could lead to new approaches for promoting remyelination and preserving axon function in MS. We hypothesize that expression of Ca2+-permeable glutamate receptors (N-methyl-d-aspartate receptors (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR)) by OPCs creates a unique pathway for communication with surrounding axons. Ca2+ is a universal signaling ion that has been shown to alter the growth and differentiation of cells in a variety of contexts, and Ca2+ changes appear to play a prominent role in guiding OPC behavior. But, the excessive activation of glutamate receptors can lead to high levels of Ca2+ in OPCs that can activate apoptotic cascades. Thus, monitoring changes in intracellular Ca2+ concentration in OPCs and OLs during healthy and diseased states can provide valuable information about the time course of intercellular Events that might go off track before the complete failure of the myelination machinery and the beginning of a nonreversible phase of neurodegeneration. Since the effects of neurotransmitter signaling on OPC/OL physiology are largely unknown, these receptors represent untapped therapeutic targets for demyelinating disorders such as MS. In short, a better understanding of the glutamate mediated neuron-glia communication can lead to new approaches for initiating repair of myelin.
DFG Programme
Research Units
