Mechanisms Governing the Viability of Axons and Neurons in the EAE Mouse Model of Multiple Sclerosis
Abstract
Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS). Myelin, oligodendrocytes, axons, and neurons are destroyed in persons with this disease. It is believed that neurodegeneration, including axon damage and neuron loss, is ultimately responsible for chronic disability in MS. MS is believed to be caused by the attacks on oligodendrocytes and myelin by the body s own immune system; however, the mechanisms by which axon damage and neuron loss occur in MS remain elusive. Currently, there is no effective therapy for MS that has an impact on protection of axons and/or neurons. One of the major challenges in MS research is to understand the mechanisms governing the viability of axons and neurons and to develop therapeutic strategies that enhance the survival of axons and neurons. The proposed research project will tackle this challenge and directly address one of the FY21 MSRP IIRA Focus Areas, namely Supports innovative mechanistic studies and translational approaches to promote axonal protection in MS and/or relevant experimental models of demyelination. A number of studies show that activation of the PERK pathway in response to endoplasmic reticulum stress, a specific intracellular stress induced by the accumulation of proteins in the secretory pathway, is a major player in regulating the viability of neurons and axons in various neurodegenerative diseases. However, the effects (beneficial or detrimental) of activation of the PERK pathway in neurons in neurodegenerative diseases are highly controversial. Similarly, the role of activation of the PERK pathway in neurons in MS remains elusive. The overall goal of this proposal is to determine the role of activation of the PERK pathway in neurons in neurodegeneration in MS and its underlying mechanisms using mouse models. We will use a state-of-the-art genetic technology to generate a novel mouse model that allows for temporally controlled activation of the PERK pathway specifically in neurons, and then determine if enhanced activation of the PERK pathway specifically in neurons prevents axon damage and neuron loss in the experimental autoimmune encephalomyelitis (EAE) model of MS. The results of this proposed study will represent the first demonstration that activation of the PERK pathway in neurons promotes the survival of axons and neurons in animal models of MS. Although it is known that NF-kappaB is a major player in regulating immune response and cell viability in MS and EAE, the role of NF-kappaB activation in neurons in these diseases remains elusive. We will generate novel mouse models that allow for controllable activation or inactivation of NF-kappaB specifically in neurons. We will then determine if increased activation of NF-kappaB specifically in neurons prevents axon damage and neuron loss in the EAE model, and if decreased activation of NF-kappaB specifically in neurons exacerbates axon damage and neuron loss in the EAE model. The results of this proposed study will represent the first demonstration that activation of the NF-kappaB pathway in neurons promotes the survival of axons and neurons in animal models of MS. It has been shown that activation of the PERK pathway can trigger NF-kappaB activation. A recent study suggests that NF-kappaB activation contributes to the protective effects of PERK activation on cells. Therefore, we will generate a mouse model that allows for controllable activation of PERK and inactivation of NF-kappaB specifically in neurons, and then determine if NF-kappaB inactivation in neurons diminishes the protective effects of PERK activation in neurons on axons and neurons in the EAE model. The results of this proposed study will represent the first demonstration that NF-kappaB activation accounts for the neuroprotective effects of the PERK pathway in neurons in animal models of MS. This work will imply that activation of the PERK-NF-kappaB pathway in neurons prevents a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210757
Entities
People
- Wensheng Lin
Organizations
- United States Army
- University of Minnesota