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The neuropathobiology of multiple sclerosis

Abstract

Chronic low-grade inflammation and neuronal deregulation are two components of a smoldering disease activity that drives the progression of disability in people with multiple sclerosis (MS). Although several therapies exist to dampen the acute inflammation that drives MS relapses, therapeutic options to halt chronic disability progression are a major unmet clinical need. The development of such therapies is hindered by our limited understanding of the neuron-intrinsic determinants of resilience or vulnerability to inflammation. In this Review, we provide a neuron-centric overview of recent advances in deciphering neuronal response patterns that drive the pathology of MS. We describe the inflammatory CNS environment that initiates neurotoxicity by imposing ion imbalance, excitotoxicity and oxidative stress, and by direct neuro-immune interactions, which collectively lead to mitochondrial dysfunction and epigenetic dysregulation. The neuronal demise is further amplified by breakdown of neuronal transport, accumulation of cytosolic proteins and activation of cell death pathways. Continuous neuronal damage perpetuates CNS inflammation by activating surrounding glia cells and by directly exerting toxicity on neighbouring neurons. Further, we explore strategies to overcome neuronal deregulation in MS and compile a selection of neuronal actuators shown to impact neurodegeneration in preclinical studies. We conclude by discussing the therapeutic potential of targeting such neuronal actuators in MS, including some that have already been tested in interventional clinical trials.

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Fig. 1: Clinical and paraclinical features of multiple sclerosis (MS).
Fig. 2: Low-grade inflammation and neuronal deregulation in multiple sclerosis (MS).
Fig. 3: Pathways of neurodegeneration in multiple sclerosis.
Fig. 4: Spiral of neuronal death and therapeutic targets.

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Acknowledgements

The authors thank all members of the Friese laboratory for the discussions. M.S.W. is funded by the Else-Kröner-Fresenius Memorial Stipend (2023_EKMS.03) and Joachim-Herz-Foundation. J.B.E is funded by the Hertie Network of Excellence in Clinical Neuroscience Fellowship. The research of M.A.F. into inflammation-induced neurodegeneration during MS at the Institute of Neuroimmunology and Multiple Sclerosis is supported by the Bundesministerium für Bildung und Forschung (16GW0308K), Deutsche Forschungsgemeinschaft (FR1720/25-1, FR1720/24-1, FR1720/11-2, FR1720/9-2, SFB1328 A16), Gemeinnützige Hertie-Stiftung (P1200091, P1210014, P1220064, P1230093), Deutsche Multiple Sklerose Gesellschaft (V6.2), Werner Otto-Stiftung (07/100), Walter und Ilse Rose-Stiftung (T0298/38958/2021) and Research Funds of the University Medical Center Hamburg-Eppendorf.

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Glossary

Assay for transposase-accessible chromatin using sequencing

(ATAC-seq). A method that allows the analysis of chromatin accessibility by sequencing of open chromatin that was tagged and fragmented by the hyperactive transposase Tn5.

Axon transections

Loss of axonal continuity (axotomy) owing to inflammation, demyelination or trauma, which leads to retrograde and Wallerian (anterograde) degeneration.

Chromatin immunoprecipitation and sequencing

(ChIP–seq). A method that identifies DNA binding sites of proteins by performing next-generation sequencing with immunoprecipitated DNA.

Disease-modifying therapies

Therapies that delay or slow down the progression of a disease; in the context of MS, currently available disease-modifying therapies consist of immunomodulatory therapies.

Excitation–inhibition balance

The excitation–inhibition balance describes the entirety of neuronal excitatory and inhibitory inputs and outputs, which is maintained at a constant ratio in steady state.

Experimental autoimmune encephalomyelitis

(EAE). An animal model of MS that is initiated by immunization of animals with myelin peptides or proteins and a strong adjuvant exerting autoreactive lymphocytes (active EAE) or by transferring these autoreactive lymphocytes into non-immunized animals (passive EAE).

External cues

Extracellular stimuli that neurons are exposed to during CNS inflammation that elicit a neuronal response.

Internal cues

Intracellular stimuli that activate neuron-intrinsic molecular pathways and trigger a neuronal response.

Iron rims

Lesions that are surrounded by an iron deposition, which can be imaged by MRI and are associated with disease progression and activated microglia and monocytes in histopathology.

Myeloid cells

Haematopoietic stem cell-derived cell types that develop from myeloid progenitor cells in contrast to the lymphoid cell lines. They comprise monocytes, tissue macrophages, microglia, dendritic cells and granulocytes.

Normal-appearing grey matter

Grey matter of people with MS that appears normal, that is, without inflammatory lesions in an MRI scan and in neuropathological specimens.

Normal-appearing white matter

White matter of people with MS that appears normal, that is, without inflammatory lesions in an MRI scan and in neuropathological specimens.

Optical coherence tomography

(OCT). Non-invasive imaging modality using light waves to take cross-sectional images of the retina.

Progression independent of relapse activity

(PIRA). Continuous disability accumulation that occurs independently of relapse activity.

Randomized clinical trial

A clinical trial wherein individuals are randomly assigned to different experimental or control groups. Randomized clinical trials are the gold standard for phase III clinical trials.

Relapse-associated worsening

(RAW). Initial increase in disability that is preceded by any relapse in the past 90 days.

Retrograde degeneration

An active form of axonal degeneration proximal to the axonal injury that includes degeneration of the neuronal somata.

Set points

Optimal target values for a regulated variable that is actively maintained during tissue homoeostasis.

Smoldering disease activity

This includes low-grade inflammation, mostly composed of activated infiltrating and CNS-resident myeloid cells, and neuronal deregulations that start early in the MS disease course and determine neurodegeneration and disability progression.

Tissue homoeostasis

Active maintenance of quantitative variables within a desirable range. Target values for these variables are defined as set points.

Unfolded protein response

(UPR). A conserved adaptive cellular stress response to reduce unfolded and misfolded protein load to maintain cell homoeostasis and viability.

Wallerian (anterograde) degeneration

An active form of axonal degeneration distal of the axonal injury. This is associated with swelling of the axon and formation of axonal spheroids.

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Woo, M.S., Engler, J.B. & Friese, M.A. The neuropathobiology of multiple sclerosis. Nat. Rev. Neurosci. (2024). https://doi.org/10.1038/s41583-024-00823-z

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