ALS Gene Expression: Key to New Treatments

Yeah it's scary. ALS doesn't just attack the body it slowly takes people away, piece by piece. One day you're walking. The next, just blinking might be a triumph. There's no cure. No magic switch. Just time ticking, and a resilience in people that feels bigger than fear.

But here's a truth I want to share with you something that's shaking up the world of ALS research: we're starting to see a pattern. Not a bunch of random mutations like scattered puzzle pieces with no picture but a common thread. A breakdown in how genes are read in the body especially a gene you've probably never heard of called UNC13A.

This gene controls how neurons talk to each other. If it goes quiet or misfires, communication shuts down. And that's when neurons start to die.

The wild part? This glitch in ALS gene expression isn't just in inherited cases. It's showing up across nearly all types of ALS even in people with no family history.

It's not a cure. Not yet. But it's a clue. A real, scientific, repeatable clue. And for the first time in a long time, that feels like permission to hope not blindly, but with purpose.

What Happens?

Let's start simple. Your body runs on proteins. But proteins don't just appear. They're built using instructions from your DNA. And the way those instructions get turned into action is called gene expression.

Think of it like a recipe book. You have the recipe for chocolate chip cookies (that's your DNA), but if someone rips out a page or skips a step (like forgetting the baking soda), you end up with a sad, flat mess.

In ALS, it's like that. The genes are often fine no typos in the DNA but somewhere between reading the recipe and mixing the batter, things go wrong. That's disrupted gene expression.

And here's the breakthrough: scientists are realizing this isn't just one chef making one mistake. It's happening across kitchens in both rare inherited forms and the more common, sporadic ALS. And UNC13A keeps showing up in the recipe logs.

So why does this matter? Because if the problem isn't always the gene itself but how it's used then we might be able to fix the process, even if we can't change the DNA.

Neurons Gone Quiet

Motor neurons are the messengers that tell your muscles to move. To speak. To breathe. And they don't talk with words they pass chemical signals called neurotransmitters. It's like a never-ending game of telephone deep inside your spine and brain.

UNC13A is the gene that makes the protein helping neurons "pass the note" correctly. It prepares the signal, packages it, and ensures it's sent at the right time. No UNC13A, no message.

Now, imagine what happens when ALS gene expression messes with this gene. The messages get delayed. They misfire. Sometimes, they don't go out at all. The muscle waits and when it doesn't get directions, it weakens. Atrophies.

And neurons? They don't like being ignored. Or overworked. They get stressed. Exhausted. Eventually, they die.

What's wild and hopeful is that this exact glitch shows up in patients with C9ORF72, SOD1, TDP-43 mutations and even in people with no known mutation at all.

In a study of gene expression in spinal tissues, researchers found consistent errors in how UNC13A was spliced like a sentence being cut in half or rearranged incorrectly before being read. Again and again. Across patients. Across genetics.

It's not just a side effect. It's a central issue. A fingerprint at the scene of the crime.

Gene by Gene

ALS isn't caused by one single gene. It's more like a web. Some genes pull harder than others, and when one breaks, it tugs on the whole structure.

Gene	Function	Expression Issue in ALS	Impact
UNC13A	Regulates neurotransmitter release at synapses	Splicing errors due to C9ORF72 or TDP-43 pathology	Neuronal communication failure
C9ORF72	RNA regulation, immune function	Repeat expansion RNA foci formation	Disrupts RNA processing, including UNC13A
TARDBP (TDP-43)	RNA splicing, stability	Mislocalized to cytoplasm loss of function	Widespread splicing errors in genes like UNC13A
SOD1	Antioxidant defense	Misfolded protein accumulation	Toxicity, but less tied to gene expression
FUS	RNA processing, transport	Cytoplasmic aggregation	Alters expression of synaptic genes
GAD2, GABRE, CALB1	Neurotransmitter balance, Ca buffering	Downregulated in spinal motor neurons	Increased excitotoxicity risk

This isn't just a list of names. These genes are part of a system and in ALS, the system is under stress. The big takeaway? It's not enough to look at what genes are mutated. We need to see how they're being used or misused. That's the heart of neuronal communication ALS research today.

The Eye Clue

Here's something that stopped me cold when I first heard it: in late-stage ALS, when the body is nearly paralyzed, patients can still move their eyes.

Think about that. Their voices are gone. Their limbs don't respond. But they can track your face across the room. Blink in answer to questions. Communicate with their gaze.

Why? Why do the neurons controlling eye movement survive when others don't?

Turns out, it's not luck. It's biology.

In a 2020 study comparing motor neurons, researchers found that eye movement neurons naturally express higher levels of protective genes:

• GAD2: Turns excess glutamate (an excitatory signal) into GABA (a calming one).
• GABRE: Helps the brain respond better to GABA.
• CALB1: Acts like a sponge for excess calcium, which can poison neurons.

These genes act like bodyguards. They reduce excitotoxicity the process where overexcited neurons burn themselves out. And in ALS, this is a major killer.

Spinal motor neurons? They don't have this shield. Their GAD2 and CALB1 levels drop. They're left exposed.

So what if we could give them the same protection? What if we could train vulnerable neurons to act more like the resilient ones?

Protection Possible?

Here's where things get exciting and human.

Scientists aren't just looking at what goes wrong. They're asking: What goes right?

In animal studies, boosting GAD2 in fruit flies with TDP-43 mutations a common ALS-related issue led to improved movement and longer survival.

It wasn't a cure. But it was a sign. A signal that biology can be nudged. That resilience can be shared.

Imagine a future where treatment doesn't just slow decline where it reprograms neurons to defend themselves. Not by attacking one gene, but by teaching cells how to survive.

This isn't science fiction. It's where ALS treatment strategies are heading.

Real Patients, Real Hope

A few years ago, most treatments focused on symptoms. Help breathe. Help eat. Help live with the decline.

Today? The goal is shifting. We're asking: Can we fix the process? Can we restore correct gene expression?

And the answer, in some cases, is already yes.

Tofersen (Qalsody), an FDA-approved drug, targets SOD1 mutations using antisense oligonucleotides (ASOs) tiny molecules that silence faulty gene expression. It doesn't fix the DNA, but it stops the toxic protein from building up.

It's not for everyone. But it's proof that targeting gene expression works. And that opens the door for similar therapies maybe ones that fix UNC13A splicing errors in non-SOD1 patients.

Clinical trials are exploring:

• ASOs for C9ORF72 to prevent toxic RNA buildup.
• Splicing modulators to fix errors in UNC13A.
• Gene therapy to deliver protective genes like CALB1 directly to motor neurons.

Some are early. Some are risky. But families are signing up. Because hope, when it has a plan, is powerful.

Hope With Care

Let's be honest. This isn't a miracle. These therapies are complex. Expensive. Hard to deliver to the nervous system. And most people with ALS don't have a known mutation their case is sporadic, with no clear genetic cause.

But here's what gives me pause in a good way: even in sporadic cases, we see the same gene expression breakdowns. The same splicing errors. The same missing protection.

Which means: one treatment may eventually help many, regardless of genetics.

We still have hurdles. Delivery. Safety. Cost. But the path forward is clearer than it's ever been.

Test or Not?

If you're facing ALS personally or with a loved one you might be thinking: Should I get genetic tested?

There's no one answer. It's deeply personal.

On one hand, testing can confirm diagnosis, open doors to clinical trials, and help family members understand their risk. On the other, it can bring emotional weight, privacy concerns, and uncertainty not all mutations mean you'll get ALS.

The ALS Association recommends talking to a genetic counselor first. No pressure. Just support.

And here's something important: even if you don't have a mutation, you might still benefit from gene-targeted therapies. Because ALS gene expression can go wrong even in healthy genes it's about how they're read, not just what they are.

Genes to Know

Over 40 genes are linked to ALS. Here are the most common, according to the ALS Association:

• C9ORF72 most common in familial ALS (~40%)
• SOD1 second most common (~1220%)
• TARDBP (TDP-43) ~4% familial, ~1% sporadic
• FUS ~5% familial
• Others: ATXN2, TBK1, NEK1, OPTN, VCP, and more

But remember: 90% of ALS is sporadic. And yet, many of these patients still show gene expression issues. That's why targeting the process not just the gene could be the real game-changer.

Beyond Symptoms

We're moving from treating symptoms to treating the root. From slowing ALS to possibly stopping it.

The future? Precision medicine. Treatments tailored to how your body expresses genes, not just your diagnosis.

That could mean:

• RNA therapies to correct splicing errors.
• Small molecules to fix misbehaving proteins like TDP-43.
• CRISPR-based tools to edit gene expression.
• Biomarkers like GAD2 levels in spinal fluid to catch ALS earlier.

The goal isn't just more time. It's better time. Less decline. More control. A life that doesn't revolve around waiting for the next loss.

You're Part of This

I want to say this gently, but with weight: progress needs you.

Seriously. Science runs on data. And for diseases like ALS, where brain and spinal tissue is hard to study, donations after death are a lifeline.

The studies we're talking about the ones that found UNC13A issues and differences in eye neurons relied on tissue from people who said: "After I'm gone, let my body help others."

That's not just donation. That's legacy.

If you're considering joining a registry or donating, know this: you're not just a patient. You're a pioneer.

Organizations like the ALS Association and Project MinE make it easy to get involved.

Final Thoughts

ALS gene expression isn't just a lab term. It's a lifeline.

From the consistent disruption in UNC13A to the protective blueprint of eye neurons, we're finally seeing patterns in the chaos. And that changes everything.

We're not there yet. But we're no longer in the dark. Therapies are emerging. Real ones. And they're built on the idea that we can fix how genes are used not just what genes we have.

If you or someone you love is walking this road, talk to your care team. About testing. About trials. About what's next.

Because every breakthrough starts the same way: with someone asking, What if?

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a healthcare professional before starting any new treatment regimen.