Major
Neuroscience
Anticipated Graduation Year
2026
Access Type
Open Access
Abstract
Multiple Sclerosis (MS) is a chronic autoimmune disorder that results in
the targeted destruction of myelinated axons within the central nervous system (CNS). Remyelination restores neuronal function
and prevents axonal degeneration, but remyelination is either incomplete or inconsistent in MS. Efforts to re-populate remyelinating oligodendrocytes will therefore advance reparative therapeutics for MS. Remyelinating oligodendrocytes develop and function in the presence of inflammatory environment in MS. It has been shown that inflammation diminishes the capacity of oligodendrocyte precursor cells (OPCs) to develop into mature oligodendrocytes and remyelinate demyelinated lesions. In addition, inflammation induced endoplasmic reticulum (ER) stress is one of the driving mechanisms leading to oligodendrocyte cell death in MS and its inflammatory mouse model experimental autoimmune encephalomyelitis (EAE). The UPR is triggered by ER stress and orchestrated by three signaling pathways: PERK, ATF6, and IRE1. Previous results showed the activation of PERK
pathway provided protection to remyelinating oligodendrocytes and promoted remyelination; however, the contributions of the other UPR pathways, including IRE1 to oligodendrocyte response in MS remains unclear. Upon stress, activated IRE1 splices XBP1 mRNA, producing XBP1s, which enhances UPR gene expression. Recent studies suggested that Xbp1s is important for normal developmental myelination, myelin maintenance and remyelination after injury in Schwann cells. Therefore, we hypothesized that targeted activation of the IRE1/Xbp1s branch of the UPR in OPC may promote OPC differentiation and enhance myelination. This study will provide a deeper understanding of the role of IRE/XBP1s on remyelination, which may lead to new rejuvenating therapeutic strategies to MS.
Faculty Mentors & Instructors
Yanan Chen, MD, PhD, Neurobiology
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
INVESTIGATING THE IMPACTS OF XBP1S OVEREXPRESSION IN OLIGODENDROCYTE PROGENTIOR CELLS IN A REMYLINATING MOUSE MODEL OF MULTIPLE SCLEROSIS
Multiple Sclerosis (MS) is a chronic autoimmune disorder that results in
the targeted destruction of myelinated axons within the central nervous system (CNS). Remyelination restores neuronal function
and prevents axonal degeneration, but remyelination is either incomplete or inconsistent in MS. Efforts to re-populate remyelinating oligodendrocytes will therefore advance reparative therapeutics for MS. Remyelinating oligodendrocytes develop and function in the presence of inflammatory environment in MS. It has been shown that inflammation diminishes the capacity of oligodendrocyte precursor cells (OPCs) to develop into mature oligodendrocytes and remyelinate demyelinated lesions. In addition, inflammation induced endoplasmic reticulum (ER) stress is one of the driving mechanisms leading to oligodendrocyte cell death in MS and its inflammatory mouse model experimental autoimmune encephalomyelitis (EAE). The UPR is triggered by ER stress and orchestrated by three signaling pathways: PERK, ATF6, and IRE1. Previous results showed the activation of PERK
pathway provided protection to remyelinating oligodendrocytes and promoted remyelination; however, the contributions of the other UPR pathways, including IRE1 to oligodendrocyte response in MS remains unclear. Upon stress, activated IRE1 splices XBP1 mRNA, producing XBP1s, which enhances UPR gene expression. Recent studies suggested that Xbp1s is important for normal developmental myelination, myelin maintenance and remyelination after injury in Schwann cells. Therefore, we hypothesized that targeted activation of the IRE1/Xbp1s branch of the UPR in OPC may promote OPC differentiation and enhance myelination. This study will provide a deeper understanding of the role of IRE/XBP1s on remyelination, which may lead to new rejuvenating therapeutic strategies to MS.