Novel Mechanisms of Neurodegeneration in Multiple Sclerosis Models
Date
2022-08-17
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0000-0002-5538-7770
Type
Thesis
Degree Level
Doctoral
Abstract
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.
Description
Keywords
Multiple Sclerosis, Heterogenous nuclear ribonucleoprotein A1 (hnRNP A1), Autoimmunity, RNA binding protein dysfunction, experimental autoimmune encephalomyelitis (EAE)
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Medicine
Program
Health Sciences