Excitotoxicity in amyotrophic lateral sclerosis: a key pathogenic mechanism

TL;DR

This paper reviews how excitotoxicity, caused by excessive glutamate, plays a central role in the progression of amyotrophic lateral sclerosis and highlights the need for new treatments.

Contribution

The paper emphasizes excitotoxicity as a key pathogenic mechanism and explores its molecular underpinnings in amyotrophic lateral sclerosis.

Findings

Excitotoxicity is driven by glutamate imbalance and calcium dysregulation in motor neurons.

EAAT2 dysfunction and oxidative stress worsen neuronal damage through excitotoxic mechanisms.

Current therapies targeting excitotoxicity are limited, highlighting the need for novel, targeted strategies.

Abstract

Amyotrophic lateral sclerosis is a complex neurodegenerative disease affecting motor neurons, characterized by the involvement of various factors, including oxidative stress, inflammatory processes, glutamate excitotoxicity, mitochondrial dysfunction, protein aggregation, axonal transport abnormalities, and apoptosis. The complexity of amyotrophic lateral sclerosis arises from its multifactorial aetiology involving diverse genetic, protein, metabolic, and cellular alterations. Mutations of different genes, such as SOD1, C9ORF72, TARDBP, and FUS, have been identified as critical contributors to disease pathophysiology through their facilitation of aberrant protein misfolding and aggregation. All these factors disrupt glutamate homeostasis, leading to calcium-mediated neurotoxicity. Under oxidative stress, motor neurons exhibit a diminished capacity to regulate calcium influx, along with impaired functioning of the mitochondria and endoplasmic reticulum, further compromising cellular integrity. Dysregulation of glutamate signalling also triggers astrocytic stress responses, leading to reduced glutamate clearance, thus worsening neuronal damage through excitotoxic mechanisms. These factors contribute to the excessive production of reactive oxygen species, which exacerbates glutamate imbalance and establishes a detrimental cycle of neuronal damage and glial dysfunction, ultimately intensifying excitotoxicity. This review aims to highlight the role of excitotoxicity in motor neuronal degeneration and to explore the molecular mechanisms underlying the pathogenesis of amyotrophic lateral sclerosis. It also examines current therapeutic approaches, including approved treatments and ongoing clinical trials to reduce excitotoxicity, while emphasizing the urgent need for novel, targeted strategies. Given the lack of definitive diagnostic tools and curative therapies, advancing our understanding of the molecular mechanisms driving excitotoxicity and neurodegeneration is, therefore, crucial for the development of more effective, disease-modifying treatments to slow amyotrophic lateral sclerosis progression.

In this study, Silva-Hucha et al. highlight excitotoxicity as a central mechanism in amyotrophic lateral sclerosis, driven by aberrant glutamate release and impaired glutamate clearance. It explores the roles of EAAT2 dysfunction, calcium dysregulation, oxidative stress, and organelle damage, underscoring the need for targeted therapies and better disease models.

Graphical AbstractFor image description, please refer to the figure legend and surrounding text.

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