p53: The guardian protein that may hold clues to ALS
- research2693
- Oct 16
- 4 min read
In every cell of the body lives a small but powerful guardian called p53, a protein that constantly checks our DNA for damage.
When it finds a problem, p53 has a choice to make:
Try to repair the damage, or
If the damage is too severe, tell the cell to self-destruct before it causes harm.
In healthy tissue, this process keeps us safe. But in certain diseases, that same protective system can become overactive, and that may be what happens in Amyotrophic Lateral Sclerosis (ALS).
Recent research has begun to uncover how p53, once considered purely protective, may actually contribute to the loss of motor neurons that defines ALS.
The Basics: What Is p53 and Why Does It Matter?
p53 acts as a cellular quality-control system. Often called “the guardian of the genome,” it helps cells survive short-term stress and prevents them from turning cancerous.
When damage or stress occurs, p53 coordinates a rapid response, pausing cell growth, boosting repair enzymes, or, in more serious cases, initiating apoptosis, the cell’s built-in self-destruct program.
In the brain and spinal cord, neurons rely on p53 to respond to stress signals. Normally, once the danger passes, p53 quietens down again. But in ALS, evidence suggests this balance breaks down.
What the research shows
Elevated p53 in ALS
Early post-mortem studies found unusually high levels of p53 in the spinal cords of people with ALS. It wasn’t just sitting idle, it was active, switching on genes that trigger cell death (Martin et al., 2000).
Genetic and cellular evidence
Recent large-scale genetic studies show that p53 signalling is one of the most upregulated pathways in ALS motor neurons — particularly in people with C9orf72 gene mutations, but also in other ALS subtypes (Ziff et al., 2023).
The connection with TDP-43
Almost all people with ALS have clumps of a protein called TDP-43 inside their neurons. Laboratory studies show that when TDP-43 builds up abnormally, it can activate p53, leading to neuronal death (Vogt et al., 2018).
What happens when p53 is turned down?
In experimental models, reducing p53 activity protected neurons from degeneration. When researchers silenced or deleted the p53 gene, motor neurons survived longer and symptoms progressed more slowly (Maor-Nof et al., 2021).
Together, these findings suggest that while p53 begins as a guardian, chronic stress in ALS may push it to become an executioner.
How Might This Happen?
Scientists don’t yet have the full answer, but several mechanisms are being explored:
DNA damage that never gets repaired: Neurons in ALS show signs of DNA injury. If the damage persists, p53 remains switched on, continually pushing cells toward self-destruction.
Oxidative stress: Motor neurons in ALS experience high levels of reactive oxygen species that damage DNA and mitochondria, keeping p53 active.
Inflammation and immune activation: Overactive immune cells in the spinal cord release inflammatory signals that amplify p53’s effects.
Toxic protein interactions: Proteins such as TDP-43 or SOD1 may directly interact with p53 or its regulators, tipping the balance toward a death signal.
These mechanisms remain areas of scientific investigation — promising, but not yet fully understood in humans.
Why This Matters
Understanding p53 in ALS gives researchers a potential new therapeutic target. If future studies can find ways to restore balance, keeping p53 protective without letting it become destructive, it could help preserve motor neurons for longer.
But this must be done carefully. p53 also prevents cancer, so the goal is not to suppress it entirely, but to help the body maintain a healthy equilibrium between protection and repair.
A Nutritional and Functional Perspective
From a nutritional and functional medicine perspective, this research highlights a broader truth about the brain and body: cellular stress and repair are two sides of the same coin.
Many of the same biological pressures that influence p53, oxidative damage, inflammation, mitochondrial stress, and poor energy metabolism, are also shaped by how we live, eat, and recover.
At You Nutrition Clinic, we work with individuals to help optimise the body’s internal environment, supporting the cellular systems that underpin neurological health and resilience.
Through personalised nutrition and lifestyle strategies, our practitioners help clients strengthen the foundations that influence how the nervous system responds to stress, energy demand, and repair.
Our work focuses on creating the best possible conditions for the body to maintain function, adapt, and protect itself over time, empowering clients to support their brain and nervous system health with confidence and understanding.
💬 Stay Connected
If you’d like to learn more, you can contact You Nutrition Clinic to speak with one of our practitioners about supporting long-term brain and nervous system health.
🧩 Connect With Us
For more insights, research updates, and practical tips on brain health and nutrition, follow us on Instagram:
Stay inspired. Stay informed. Support your brain. 🧠
References
Martin, L. J., et al. (2000). p53 is abnormally elevated and active in the CNS in human amyotrophic lateral sclerosis. Experimental Neurology, 163(1), 123–131. https://doi.org/10.1006/exnr.2000.7352
Ziff, O. J., et al. (2023). Integrated transcriptome landscape of ALS identifies robust upregulation of p53 signalling. Nature Communications, 14, 2035. https://doi.org/10.1038/s41467-023-37630-6
Vogt, M. A., et al. (2018). TDP-43 induces p53-mediated cell death in neural progenitor cells. Scientific Reports, 8, 6656. https://doi.org/10.1038/s41598-018-26397-2
Maor-Nof, M., et al. (2021). p53 is a central regulator driving neurodegeneration caused by C9orf72 expansion. Nature Neuroscience, 24(6), 859–868. https://doi.org/10.1038/s41593-021-00861-7
Browne, S. E., & Beal, M. F. (2022). Mitochondrial dysfunction in ALS and MS. Free Radical Biology and Medicine, 188, 44–59. https://doi.org/10.1016/j.freeradbiomed.2022.01.017
Comments