Novel Mechanisms of Neurodegeneration in Multiple Sclerosis Models

Neurodegeneration, the progressive loss of function or structure to neurons and axons, underlies permanent disability in multiple sclerosis (MS); yet its mechanisms are incompletely understood. Historically, the autoimmune response in MS was thought to target myelin products causing demyelination but recent data indicates autoimmunity to several intraneuronal antigens, including the RNA binding protein (RBP) heterogenous nuclear ribonucleoprotein A1 (hnRNP A1), as contributors to neurodegeneration. Previous research identified that anti-hnRNP A1 antibodies are taken up by neuron-like cells in vitro resulting in hnRNP A1 mislocalization and stress granule formation. Anti-hnRNP A1 antibody addition to mice with experimental autoimmune encephalomyelitis (EAE) resulted in exacerbated clinical disease, and increased neurodegeneration, the mechanisms of which are unknown. We hypothesized that anti-hnRNP A1 antibodies would be taken up by neurons, induce hnRNP A1 dysfunction in the form of its nuclear-cytoplasmic mislocalization, stress granule formation, and altered RNA expression, which might trigger neurodegeneration in models of MS. We tested this hypothesis by treating mice with EAE, primary embryonic cortical neurons, or neuronal cell lines with anti-hnRNP A1 antibodies (which overlap with the immunodominant epitope of MS IgG) and examining them for antibody localization and markers of hnRNP A1 dysfunction and neurodegeneration over time. We found that in in vivo and in vitro MS models, anti-hnRNP A1 antibodies (compared to IgG control) are preferentially taken up by clathrinmediated endocytosis, induce hnRNP A1 cytoplasmic-mislocalization followed by subsequent stress granule formation and altered RNA expression. This anti-hnRNP A1 antibody-mediated hnRNP A1 dysfunction then triggers the activation of necroptosis (a cell death pathway) and subsequent neurodegeneration (characterized by loss of neurons and neurites). These findings implicate an autoantibody response characteristic of MS as an important contributor to neurodegeneration and permanent disability. Further, it demonstrates the importance of RBP dysfunction as an underlying mechanism of neurodegeneration. Taken together, we identified a novel antibody-mediated mechanism of neurodegeneration, which may be targeted to inhibit neurodegeneration and prevent permanent disability in persons living with MS

The Potential Contribution of Dysfunctional RNA-Binding Proteins to the Pathogenesis of Neurodegeneration in Multiple Sclerosis and Relevant Models

Neurodegeneration in multiple sclerosis (MS) is believed to underlie disease progression and permanent disability. Many mechanisms of neurodegeneration in MS have been proposed, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and RNA-binding protein dysfunction. The purpose of this review is to highlight mechanisms of neurodegeneration in MS and its models, with a focus on RNA-binding protein dysfunction. Studying RNA-binding protein dysfunction addresses a gap in our understanding of the pathogenesis of MS, which will allow for novel therapies to be generated to attenuate neurodegeneration before irreversible central nervous system damage occurs

The Potential Contribution of Dysfunctional RNA-Binding Proteins to the Pathogenesis of Neurodegeneration in Multiple Sclerosis and Relevant Models

Neurodegeneration in multiple sclerosis (MS) is believed to underlie disease progression and permanent disability. Many mechanisms of neurodegeneration in MS have been proposed, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and RNA-binding protein dysfunction. The purpose of this review is to highlight mechanisms of neurodegeneration in MS and its models, with a focus on RNA-binding protein dysfunction. Studying RNA-binding protein dysfunction addresses a gap in our understanding of the pathogenesis of MS, which will allow for novel therapies to be generated to attenuate neurodegeneration before irreversible central nervous system damage occurs.</jats:p

Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics

AbstractThere are over 15 disease-modifying drugs that have been approved over the last 20 years for the treatment of relapsing–remitting multiple sclerosis (MS), but there are limited treatment options available for progressive MS. The development of new drugs for the treatment of progressive MS remains challenging as the pathophysiology of progressive MS is poorly understood.The progressive phase of MS is dominated by neurodegeneration and a heightened innate immune response with trapped immune cells behind a closed blood–brain barrier in the central nervous system. Here we review microglia and border-associated macrophages, which include perivascular, meningeal, and choroid plexus macrophages, during the progressive phase of MS. These cells are vital and are largely the basis to define lesion types in MS. We will review the evidence that reactive microglia and macrophages upregulate pro-inflammatory genes and downregulate homeostatic genes, that may promote neurodegeneration in progressive MS. We will also review the factors that regulate microglia and macrophage function during progressive MS, as well as potential toxic functions of these cells. Disease-modifying drugs that solely target microglia and macrophage in progressive MS are lacking. The recent treatment successes for progressive MS include include B-cell depletion therapies and sphingosine-1-phosphate receptor modulators. We will describe several therapies being evaluated as a potential treatment option for progressive MS, such as immunomodulatory therapies that can target myeloid cells or as a potential neuroprotective agent.</jats:p

Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics

There are over 15 disease-modifying drugs that have been approved over the last 20 years for the treatment of relapsing–remitting multiple sclerosis (MS), but there are limited treatment options available for progressive MS. The development of new drugs for the treatment of progressive MS remains challenging as the pathophysiology of progressive MS is poorly understood. The progressive phase of MS is dominated by neurodegeneration and a heightened innate immune response with trapped immune cells behind a closed blood–brain barrier in the central nervous system. Here we review microglia and border-associated macrophages, which include perivascular, meningeal, and choroid plexus macrophages, during the progressive phase of MS. These cells are vital and are largely the basis to define lesion types in MS. We will review the evidence that reactive microglia and macrophages upregulate pro-inflammatory genes and downregulate homeostatic genes, that may promote neurodegeneration in progressive MS. We will also review the factors that regulate microglia and macrophage function during progressive MS, as well as potential toxic functions of these cells. Disease-modifying drugs that solely target microglia and macrophage in progressive MS are lacking. The recent treatment successes for progressive MS include include B-cell depletion therapies and sphingosine-1-phosphate receptor modulators. We will describe several therapies being evaluated as a potential treatment option for progressive MS, such as immunomodulatory therapies that can target myeloid cells or as a potential neuroprotective agent.Medicine, Faculty ofNon UBCMedicine, Department ofNeurology, Division ofPathology and Laboratory Medicine, Department ofReviewedFacultyResearcherOthe