The Tale of a Tragedy: ALS, the Death Sentence

I am not sure if “ALS” sends the same shivers down your spine as it does mine, but I am certain it will by the end of this article. Amyotrophic Lateral Sclerosis, or ALS, is a debilitating neurodegenerative disease, characterised by motor neuron dysfunction.

This may sound like medical jargon for some overblown disease, but is a tragic understatement of the horror that is ALS. 

Why is ALS so terrible?

Firstly, the age of onset for this disease is wide. Typically striking individuals aged over 45, ALS has afflicted individuals as young as 20! In comparison, Alzheimer’s and Parkinson’s, the most familiar neurodegenerative diseases that steal the spotlight and research funding, typically begin after 65 years.

ALS can mercilessly target the relatively younger population, full of dreams and ambitions. Not only that, ALS progresses rapidly, leading to respiratory failure within a mere 2-5 years of onset. That is to say, ALS crushes those dreams and ambitions like a soap bubble. Indeed, a diagnosis of ALS in the hospital is nothing short of a death sentence in the court.

A prominent case of ALS is the revolutionary theoretical physicist, Sir Stephen Hawking, whom ALS afflicted at just 21. Like a serial killing machine, ALS steadily began to paralyse his muscles, including those for speaking, breathing, and swallowing. This rendered him immobile, confined to a wheelchair, unable to even speak. Nonetheless, Sir Stephen Hawking persisted, defying the rapid death sentence and living onto the ripe old age of 76, 55 years after receiving his earth-shattering diagnosis. He used a computer speech synthesiser to communicate his brilliant ideas & continue his revolutionary work in cosmology.

Despite ALS attempting to strip away from our world a genius and his invaluable contributions to cosmology, research into ALS treatment has been appallingly underfunded. Thus, ALS remains incurable, with 90-95% of cases being idiopathic (having an unknown cause), only adding fuel to the nightmare.

The Unforgiving Progression

ALS begins silently. First, a twitch. Then weakness. Eventually, it spreads. The disease selectively targets motor neurons, cells that control voluntary muscles. Both upper and lower motor neurons degenerate, leading to muscle atrophy and eventually respiratory failure. Though ALS is idiopathic, emerging science has mapped out the underlying chaos in some detail.

Apart from genetic predisposition, mitochondrial dysfunction, oxidative stress, excitotoxicity from glutamate, protein aggregation, and defective axonal transport are all at play. These aren’t isolated malfunctions; they are deeply intertwined, creating a vicious cycle that accelerates neurodegeneration.

Genetics: The First Domino

About 90-95% of ALS cases are sporadic, while the other 5-10% are familial, tied to identifiable mutations. Mutations in four genes; SOD1, C9orf72, TARDBP, and FUS; account for most genetic ALS cases. These mutations sabotage basic cellular housekeeping. They disrupt protein folding, impair RNA handling, and ignite processes that should remain dormant.

In SOD1 mutations, for example, the antioxidant enzyme misfolds and becomes toxic. C9orf72 expansions lead to the accumulation of abnormal RNA and toxic dipeptide repeat proteins. These mutations actively fuel the breakdown of cellular systems.

Protein Aggregation: From Misfolding to Mayhem

Misfolded proteins, especially TDP-43, accumulate in motor neurons like junk in a broken factory. Normally involved in RNA processing, TDP-43 becomes trapped in the cytoplasm, forming aggregates that block critical cell functions. Proteins are supposed to fold precisely; when they don’t, the cell tries to remove them.

But in ALS, those cleanup systems, like the ubiquitin-proteasome and autophagy-lysosome pathways, are overwhelmed. This is not just clutter. These aggregates disrupt organelle function, block nuclear transport, and impair cell survival signaling.

RNA Dysfunction

TDP-43 and FUS aren't just proteins, they are RNA-binding proteins essential for regulating gene expression. When mutated or mislocalized, they mismanage RNA splicing, transport, and stress granule dynamics. Aberrant RNA metabolism changes the expression of dozens, maybe hundreds, of genes necessary for neuron survival. This adds a layer of complexity that makes ALS particularly insidious: disruption happens at the very level of genetic messaging.

Mitochondrial Breakdown

Motor neurons are large, energy-hungry cells. They rely on mitochondria to fuel their extended axons and synaptic terminals. But in ALS, mitochondria become swollen, fragmented, and dysfunctional. They fail to generate enough ATP, poorly manage calcium, and release harmful reactive oxygen species (ROS).

Mutant SOD1 and TDP-43 proteins physically associate with mitochondria, disturbing their membrane integrity. This creates an energy vacuum and a buildup of toxic byproducts, conditions ripe for cell death.

Oxidative Stress: A Slow Burn

With mitochondria faltering, oxidative stress surges. ROS damage lipids, proteins, and DNA, compounding the cellular injury. Normally, antioxidants would buffer this damage, but ALS motor neurons lack sufficient antioxidants to respond. The redox imbalance, especially from mutant SOD1, pushes cells toward apoptosis or necrosis. It’s a slow burn, where every breath and muscle contraction pushes the cell closer to collapse.

Glutamate Excitotoxicity: Death by Overstimulation

Glutamate, the brain’s primary excitatory neurotransmitter, becomes toxic in excess. In ALS, astrocytes fail to remove it efficiently, leading to a flood of glutamate in synaptic spaces. This overstimulates NMDA and AMPA receptors on motor neurons, letting in too much calcium and triggering cell death pathways.

Cortical hyperexcitability often precedes symptoms, suggesting that excitotoxicity is an early, perhaps initiating, factor in ALS pathology.

Neuroinflammation: When Helpers Become Killers

Astrocytes and microglia, the central nervous system’s support cells, go rogue in ALS. Instead of buffering stress and clearing debris, they start to promote inflammation, as they release cytokines, complement proteins, and reactive nitrogen species that further damage motor neurons. This is a self-sustaining loop. Dying neurons activate glia, which in turn kill more neurons.

Axonal Transport and NMJ Breakdown

Neurons depend on motor proteins to ferry organelles, RNA, and nutrients along their long axons. In ALS, this transport system breaks down. Mitochondria pile up. RNA granules don’t reach their targets. This creates a “dying-back” pattern, where neuron endings at neuromuscular junctions (NMJs) degenerate first, followed by the cell body.

Without functioning NMJs, muscles weaken and waste away, accelerating paralysis.

Endoplasmic Reticulum Stress: Further Folding Failure

Misfolded protein aggregates clog the endoplasmic reticulum (ER), triggering a chronic unfolded protein response (UPR). While it is initially a protective response, the UPR turns toxic when prolonged as it activates stress sensors and apoptotic pathways in both neurons and muscle cells. This internal emergency broadcast doesn’t save the cell but sounds the alarm until the entire system shuts down.

A Multi-Front War

ALS isn’t caused by one broken part. It’s a system-wide failure. Genetic mutations light the match, but it's the interaction of protein aggregation, RNA dysfunction, mitochondrial decay, excitotoxicity, and neuroinflammation that fuels the fire.

These mechanisms form a tight positive feedback loop: misfolded proteins damage mitochondria, triggering oxidative stress, which activates glia, which secrete more toxins, which disrupt axons, which cause further misfolding, and on goes the vicious cycle.

Conclusion and Future Directions

Diagnosis relies on clinical criteria supported by EMG, imaging, and genetic testing. The emergence of neurofilament light chain (NfL) as a biomarker offers a measurable correlate of disease progression.

Therapeutic options remain limited. Riluzole, edaravone, and taurursodiol offer modest benefits. Newer options like tofersen, an antisense oligonucleotide targeting SOD1, show promise in genetic subsets. Stem cell therapies and personalized gene-targeting approaches are in development.

The reality is that targeting a single pathway isn’t enough. Future therapies must tackle ALS from multiple angles: restoring proteostasis, repairing mitochondria, calming neuroinflammation, and rebalancing neurotransmission. Precision medicine, customized to the molecular profile of each patient, offers hope.

ALS is more than a disease, it’s a collapse of the nervous system’s integrity. Understanding its mechanisms is not just about science. It’s about urgency, clarity, and ultimately, finding a way to stop the tale from ending in tragedy.

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Image Credit: https://projectcbd.org/medical-conditions/als/