Abstract

Background:

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterised by a progressive loss of upper and lower motor neurons (MNs), for which no curative treatment exists. Traditionally regarded as a neuron-centric disease, recent evidence now recognises the inter-glial and glial-neuronal molecular pathways involved in the disease pathogenesis. This highlights the prerequisite for integrative pre-clinical modelling to facilitate the effective translation of novel therapeutic avenues targeting non-neuronal cellular mechanisms.

Objectives:

This literature review examines the role of non-neuronal cells in ALS, including their dual neuroprotective and neurotoxic functions. It also evaluates emerging therapeutic strategies such as antisense oligonucleotides, gene therapy, stem cell-based approaches, and immunomodulation.

Methods:

A targeted literature review was conducted using PubMed, Embase, Scopus, Cochrane Library, and ClinicalTrials.gov databases, identifying relevant studies published up to 2025. Eligible studies included case-control studies, reviews, pre-clinical and clinical trials. Results were critically appraised as per CASP guidelines. 

Results:

Cell autonomous and non-cell autonomous neurotoxic processes within the central and peripheral nervous system contribute to the selective degeneration of MNs in ALS. Inhibition of reactive astrogliosis slowed disease progression via targeted small-molecule therapy and knockout of pro-inflammatory microglial cytokines, prolonging the lifespan in rodent models. Overexpression of Jun, a neurotrophic transcription factor of the neuroprotective phenotype of Schwann cells (SCs), leads to severe hypomyelination in SOD1 mice, thereby worsening motor function. The abnormal interposition of terminal SCs in the neuromuscular junction presents a novel therapeutic target. Natural killer cell depletion transiently improved muscle strength in a patient with ALS and extended the survival of SOD1 and TDP43 mice.

Conclusion:

Evidence from experimental ALS models principally replicates the activation of glial cells and infiltration of peripheral immune cells in postmortem studies. Ongoing clinical trials target non-neuronal cellular mechanisms to modulate the pro-inflammatory neuronal environment. Despite delaying disease progression, clinical translation in human models yields limited clinical benefits.