Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons in the brain and spinal cord. These nerve cells are responsible for controlling voluntary muscle movement, including walking, speaking, and breathing. As motor neurons degenerate and die, they lose the ability to send signals to muscles, leading to muscle weakness, atrophy, and eventually paralysis. ALS is a complex disorder, with most cases being sporadic, while about 10% are familial due to genetic factors. The disease progresses over time, and while there is currently no cure, treatments focus on managing symptoms and slowing disease progression.
Understanding ALS Pathways
In ALS, a “pathway” refers to interconnected biological processes at molecular and cellular levels contributing to disease onset and progression. ALS involves multiple dysfunctional pathways, where disrupted cellular processes lead to motor neuron degeneration.
Genetic factors can initiate these dysfunctional pathways, as seen in familial ALS with specific gene mutations. Environmental influences are also believed to play a role, though exact causes remain largely unknown in sporadic cases. Understanding these biological pathways is important for identifying therapeutic targets.
Major Molecular Pathways
Protein Misfolding and Aggregation
A key feature of ALS is abnormal protein inclusions from misfolding and aggregation. TAR DNA-binding protein 43 (TDP-43) is a prominent example, forming cytoplasmic aggregates in most ALS cases. Normally, TDP-43 is nuclear and processes RNA, but its mislocalization and aggregation impair function and cause toxicity.
Superoxide dismutase 1 (SOD1) is another implicated protein, especially in familial ALS, where mutations cause misfolding and aggregation. These misfolded SOD1 proteins contribute to cellular damage and mitochondrial dysfunction. Fused in Sarcoma (FUS) is also an RNA-binding protein whose mutations are associated with ALS, leading to mislocalization and aggregation.
RNA Dysregulation
Issues with RNA processing, transport, and translation contribute to ALS pathogenesis. TDP-43 and FUS, as RNA-binding proteins, are involved in RNA metabolism. Mutations in these proteins disrupt these functions, altering gene expression and impairing cellular processes.
For instance, cytoplasmic mislocalization of TDP-43 reduces its nuclear levels, leading to aberrant splicing of genes like stathmin-2, which affects motor neuron axonal health. Similarly, C9orf72 mutations can form toxic RNA species that sequester RNA-binding proteins and disrupt RNA processing.
Excitotoxicity
Excitotoxicity describes nerve cell damage or death from excessive stimulation by neurotransmitters like glutamate. Motor neurons in ALS are vulnerable due to high glutamate concentrations in the synaptic space, from increased release or impaired reuptake.
Reduced function of glutamate transporters, like EAAT2 on astrocytes, is observed in many ALS patients, leading to glutamate accumulation outside neurons. This excessive glutamate overstimulates motor neuron receptors, causing an influx of calcium ions that triggers neuronal damage and death.
Mitochondrial Dysfunction
Mitochondria generate energy for cell survival. In ALS, impaired mitochondrial function is an early event contributing to disease progression. This dysfunction manifests as reduced energy production and excessive reactive oxygen species (ROS), also known as oxidative stress.
Oxidative stress damages mitochondrial DNA, membranes, and proteins, further impairing function and leading to cell death. Mutations in genes like SOD1, FUS, and TDP-43 are linked to mitochondrial damage and increased oxidative stress, creating a destructive cycle that exacerbates neuronal damage.
Neuroinflammation
Neuroinflammation involves the activation of glial cells, such as astrocytes and microglia, in the central nervous system. While these cells normally support neurons, in ALS, they shift to a reactive state that contributes to neuronal damage. Reactive astrocytes produce inflammatory proteins called cytokines that enhance disease progression.
Microglia, the brain’s immune cells, can adopt protective or neurotoxic roles. As ALS progresses, microglia increasingly adopt a pro-inflammatory and neurotoxic phenotype, releasing high levels of pro-inflammatory cytokines, reactive oxygen species, and nitric oxide, which further promote motor neuron loss.
Cellular Consequences of Pathway Dysfunction
Dysregulation in these molecular pathways collectively leads to motor neuron degeneration and death. When proteins like TDP-43, SOD1, or FUS misfold and aggregate, they form toxic clumps that disrupt normal cellular operations. This accumulation interferes with protein degradation and impairs essential molecule transport within motor neuron axons.
Issues with RNA processing, transport, and translation mean motor neurons cannot produce necessary proteins, leading to imbalances and a dysfunctional cellular environment. Excitotoxicity further damages motor neurons by overwhelming them with calcium ions, triggering destructive events.
Mitochondrial dysfunction deprives motor neurons of energy and increases oxidative stress, making them vulnerable to damage. As cellular insults accumulate, motor neurons become unhealthy and die. Non-neuronal cells like astrocytes and microglia, initially supportive, often become reactive as the disease progresses, contributing to a toxic environment that amplifies neuronal injury.
Pathway-Targeted Therapies
Understanding the complex pathways in ALS is important for developing effective treatments that intervene at specific points of dysfunction. Current strategies aim to slow disease progression or alleviate symptoms by targeting these molecular and cellular mechanisms.
Riluzole, an FDA-approved drug, primarily reduces glutamate levels and excitotoxicity, protecting motor neurons from excessive stimulation. Edaravone, another approved medication, acts as a free radical scavenger, targeting oxidative stress by reducing reactive oxygen species that contribute to cellular damage.
Emerging therapeutic approaches explore more targeted interventions, especially for familial ALS with known genetic mutations. Gene therapies, such as those for SOD1 mutations, aim to silence the production of toxic SOD1 protein using antisense oligonucleotides (ASOs). Tofersen, an ASO, is approved for ALS patients with SOD1 mutations, binding to SOD1 mRNA to inhibit toxic protein production. Other experimental treatments are also under investigation, including those correcting pathway defects like integrated stress responses or mitochondrial dysfunction.