Imagine your body as a relay race. The brain is the team captain, guiding the runners (motor neurons) to pass the baton (signals) to the muscles. These runners (motor neurons) are critical for moving, walking, and performing everyday tasks, passing the baton smoothly from one to the other. However, in amyotrophic lateral sclerosis (ALS), these runners start to slow down, and the baton (signals) gets dropped, leading to muscle weakness, loss of coordination, and ultimately paralysis.
But how far are we from the finish line where we can say we’ve cured ALS? The race is ongoing, but new breakthroughs suggest we’re getting closer.
Why Is Early Diagnosis So Important?
Just like in a relay race, noticing when a runner starts to slow down can help the team make adjustments and prevent disaster. Early diagnosis in ALS is crucial for slowing the disease’s progression, but it’s often delayed.
Why Is ALS So Hard to Diagnose?
- Early Symptoms Are Subtle: The initial symptoms of ALS can be like a runner showing slight fatigue. You might notice things like weakness in your hands, a slight stumble when walking, or difficulty swallowing—signs that can easily be overlooked.
- Getting the Right Diagnosis: Since ALS shares symptoms with other diseases, it often takes multiple doctor visits before the correct diagnosis is made. This “passing the baton” between specialists can delay the process.
- Look-Alike Diseases: Other conditions, such as certain neuropathies or spinal issues, can mimic ALS, making it difficult to identify early on.
The result is that the race is already off course by the time doctors can make a proper diagnosis.
Understanding ALS: Genetics and RNA – The Coaches of the Race
In ALS, the motor neurons (runners) fail to pass the baton effectively due to underlying genetic issues and problems with the instructions (RNA) that guide the race. Scientists are focusing on these genetic and RNA-based causes to understand the disease better and develop treatments.
Genetics: The Mistakes in the Instructions
Think of your motor neurons as athletes who depend on their coaching strategy (genes) to perform well. When there are errors in the instructions, the runners fail.
Genetic Mutations: Certain genetic mutations are linked to ALS. For example, C9ORF72, a gene known for its association with ALS, is like a coach giving the wrong instructions to the runners. These instructions cause motor neurons to deteriorate and function improperly. Research has shown that repeat expansions in the C9ORF72 gene are a frequent cause of ALS and frontotemporal dementia (FTD).
C9ORF72 and Mitochondrial Dysfunction: Studies have revealed that mitochondrial dysfunction plays a key role in the pathology of C9ORF72-linked ALS. Mitochondria are the motor neurons’ energy powerhouses, and when they malfunction, it’s like the runners running out of steam mid-race. Additionally, endoplasmic reticulum (ER) stress contributes to the progression of ALS. The ER helps manage the proteins in the cells, and when it’s overloaded, the runners (motor neurons) can’t function properly.
Protein Misfolding and Accumulation: These genetic mistakes cause proteins to misfold and build up inside the motor neurons, like runners getting tangled up with each other and failing to pass the baton smoothly. This disruption accelerates ALS progression.
RNA: The Coaches of the Race
RNA is like the coach’s playbook that helps guide the players. When RNA doesn’t work properly, the motor neurons don’t get the right instructions, and the runners fall behind.
MicroRNAs (miRNAs): These tiny molecules act as coaches, telling motor neurons how to survive. In ALS, malfunctioning miRNAs can lead to the failure of motor neurons. But the good news? These miRNAs could also serve as biomarkers to help us detect ALS earlier and even provide new targets for treatment.
Long Non-Coding RNAs (lncRNAs): These larger molecules help organize the race and ensure everything runs smoothly. Disruptions in lncRNAs have been linked to ALS, and understanding their role could lead to innovative treatments.
Next-Generation Sequencing (NGS): Advanced tools like NGS have allowed scientists to delve deeper into ALS’s genetic underpinnings, identifying rare genetic variants and RNA-based mechanisms that contribute to ALS. This insight is paving the way for targeted genetic therapies like antisense oligonucleotides (ASOs) that can fix faulty RNA and slow the progression of ALS.
💡For more insight on Next-Generation Sequencing, click here.
The Treatments: Slowing Down the Race, But Can We Win?
There’s currently no cure for ALS, but research is pushing forward with treatments to slow down the disease and offer hope for better outcomes. We’re not at the finish line yet, but there’s a strong push to get there.
Current ALS Treatments:
Riluzole: The first FDA-approved drug for ALS, Riluzole works by reducing glutamate levels in the brain, helping protect motor neurons. It’s like providing runners with a bit more energy to keep going.
Edaravone: This antioxidant may slow the progression of ALS in its early stages. It helps reduce oxidative stress, acting as a buffer to keep the motor neurons from getting damaged too quickly.
AMX0035: This combination of two drugs targets mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which are crucial factors in ALS. It’s like giving the runners the best equipment to keep them from getting too tired too fast.
A New Player in the ALS Race: C9ORF72 & Kaempferol:
One of the most promising breakthroughs comes from the study of a gene called C9ORF72. This gene is responsible for a significant portion of ALS cases, and researchers have been investigating how problems with C9ORF72 contribute to ALS.
When C9ORF72 has a repeat expansion (think of it like a repeating error in the instructions), it causes mitochondrial dysfunction and chronic ER stress—two major obstacles for motor neurons. In simpler terms, the runners are not only getting bad instructions, but they’re also being weighed down by faulty equipment and too much stress.
Now, researchers are looking at kaempferol, a naturally occurring flavonoid found in some plants, as a potential treatment to help resolve these issues in C9ORF72-linked ALS. In a recent study, kaempferol was shown to improve motor neuron health in both preclinical rodent and human models of ALS caused by the C9ORF72 gene. Here’s how it works:
- Mitochondrial Protection: Kaempferol helps normalize mitochondrial calcium uptake, restoring the motor neurons’ power sources, and allowing them to function better.
- Reducing ER Stress: It also helps resolve the stress the ER places on the motor neurons, essentially giving them a break so they can keep running.
- Neuroprotection: In mice, kaempferol treatment diminished motor neuron degeneration and improved motor function. This is like giving the runners a new strategy that allows them to race more efficiently without getting worn out.
The Mechanism Behind Kaempferol’s Action
Kaempferol works through a specific pathway known as iP3R-VDAC1, which regulates how calcium moves within mitochondria, and it helps manage the stress in motor neurons. Essentially, it reduces the burden on motor neurons, allowing them to function for longer periods and delay the progression of ALS.
💡 For more insight into this research paper, click here
What’s Next in ALS Research? The Road Ahead
While there’s still no cure for ALS, the promising findings with kaempferol, along with genetic therapies like Tofersen for SOD1 mutations, suggest that breakthroughs are on the horizon. Here are some of the key areas where research is making strides:
🍀 Genetic Therapies: Therapies like Tofersen, which targets the SOD1 gene, show that fixing specific genetic errors in ALS may be a viable approach to slowing or stopping the disease.
🔗 Read the latest research (Feb 2025)
🍀 Stem Cells and Neurorestoration: Stem cell therapies aim to replace damaged motor neurons and restore lost function, offering a potential way to heal the racecourse when it’s been damaged.
🔗 Read the latest research (Aug 2024)
🍀 Better Diagnostic Tools: Biomarkers like neurofilament proteins are helping scientists detect ALS early, much like recognizing when a runner begins to tire before it’s too late.
🔗 Read the latest research (Feb 2025)
🍀 RNA-Based Therapies: Advances in RNA-based therapies, like antisense oligonucleotides (ASOs), are showing great promise in treating ALS by targeting and correcting faulty RNA instructions. Qalsody (Tofersen), a therapy for SOD1-related ALS, is already under evaluation for approval.
🔗 Read the latest research (Oct 2024)
The Finish Line: How Close Are We to a Cure?
The journey toward an ALS cure is ongoing, but the progress we’re seeing today brings hope for the future. Advances in genetics, RNA biology, and targeted therapies like kaempferol are moving us closer to effective treatments, and possibly a cure. Research is uncovering ways to target ALS at the genetic and molecular level, with therapies now being developed to slow or even reverse the disease.
While the race is far from over, there’s real reason to stay hopeful. Research is making huge strides, and treatments like Tofersen for SOD1 mutations, along with studies into natural compounds, offer optimism. This research is about more than just data—it’s about improving lives and finding ways to manage or halt disease progression.
To those living with ALS: your resilience and hope are driving this progress. We’re one step closer to a future where ALS no longer defines your journey.
