Neuropathobiology of Multiple Sclerosis: Exploring the Intersection of Genetics and Neurodegeneration

The article "The neuropathobiology of multiple sclerosis" by Marcel S. Woo, Jan Broder Engler, and Manuel A. Friese, published in Nature Reviews Neuroscience, explores the complex mechanisms underlying neurodegeneration in multiple sclerosis (MS), highlighting the need for neuron-centric therapeutic strategies to address the unmet clinical need of halting chronic disability progression.

Introduction: The Challenge of Predicting MS Progression
Multiple sclerosis (MS) is characterized by complex immune-mediated and neurodegeneration in the central nervous system (CNS), affecting approximately 2.8 million individuals worldwide. While current therapies address acute inflammatory relapses, there is a critical need to develop treatments for the progressive, smoldering disease activity that contributes to long-term disability. The article emphasizes the dual factors of inflammation and neuron-intrinsic deregulation, which together drive MS pathology. These factors lead to widespread neurodegeneration, particularly in the grey matter, contributing to cognitive impairment, fatigue, and other neurological deficits beyond motor and sensory symptoms.

Neurodegeneration and Progression
Traditional MS classifications (relapsing-remitting, secondary progressive, and primary progressive MS) are challenged by the discovery of progression independent of relapse activity (PIRA), a process observed in all MS subtypes, even early in the disease. Studies such as the OPERA trials and the Novartis–Oxford MS data pool suggest that PIRA is a major contributor to long-term disability, emphasizing the need to shift therapeutic focus from merely suppressing relapses to preventing the smoldering neurodegeneration underlying progressive MS. Neuroimaging techniques have revealed significant cortical grey matter atrophy, which correlates more closely with disease progression than white matter lesions, thus revising the long-standing reliance on MRI findings for monitoring disease activity.

Molecular Mechanisms of Neurodegeneration
The neuronal response to MS pathology involves several mechanisms, categorized as initiators and amplifiers of neurodegeneration. Ion dysregulation and excitotoxicity are early responses to the inflammatory environment, where neurons suffer from disrupted ion homeostasis and glutamate toxicity. This leads to mitochondrial dysfunction, calcium overload, and oxidative stress, which collectively initiate neuronal injury. The role of excitotoxicity, driven by the excessive activation of ionotropic glutamate receptors (GRIs), is well-documented in MS, contributing to synaptic loss and eventual neuronal death. Furthermore, mitochondrial dysfunction is central to MS progression, as inflammation impairs the electron transport chain and depletes neuronal ATP, leading to increased reactive oxygen species (ROS) and further neuronal damage.

Neuronal Deregulation and Epigenetics
The article also discusses the epigenetic dysregulation triggered by chronic neuroinflammation. Epigenetic marks, such as DNA methylation and histone modifications, influence the transcriptional dynamics in neurons, contributing to the long-term changes observed in MS. For example, the histone methyltransferase G9a promotes a repressive epigenetic environment that sensitizes neurons to ferroptosis, a form of iron-dependent cell death prevalent in MS pathology. Understanding how inflammation-induced epigenetic changes affect neuronal resilience offers promising therapeutic avenues for mitigating disease progression.

Neuronal Immune Signaling
During MS, neurons themselves contribute to the CNS inflammatory environment by producing immune modulators like chemokines and cytokines. For instance, interferon-γ (IFNγ) stimulates neurons to secrete CCL2, which recruits immune cells that exacerbate neuronal damage. These findings suggest that neurons play an active role in shaping their own inflammatory milieu, highlighting the complex interplay between neurodegeneration and immune regulation.

Therapeutic Strategies
The review concludes by exploring potential neuron-directed therapies aimed at mitigating neurodegeneration in MS. Modulation of ion channels, especially glutamate receptors and calcium channels, is a promising therapeutic target. While current clinical trials, such as the MS-SMART trial, have yielded mixed results, the authors highlight the need for more targeted interventions that focus on neuron-intrinsic mechanisms. Emerging therapies, including inhibitors of necroptosis and ferroptosis, as well as agents aimed at enhancing mitochondrial function, are being investigated for their potential to slow disease progression.

In summary, this comprehensive review underscores the importance of neuron-specific research in MS. While immunomodulatory therapies have successfully reduced relapse rates, addressing the smoldering neurodegeneration that drives long-term disability requires a deeper understanding of the neuron-intrinsic factors involved in disease progression. The article calls for a paradigm shift towards targeting neuronal resilience and identifying new therapeutic strategies to counteract the devastating effects of MS on the CNS.

References:
Woo, M.S., Engler, J.B. & Friese, M.A. The neuropathobiology of multiple sclerosis. Nat. Rev. Neurosci. 25, 493–513 (2024).