What Do Schizophrenia and ALS Have In Common?
In an era of increasing need for understanding mental health and neurodegenerative conditions, identifying links between the two could revolutionise our approach towards clinical care.
My name is Lili, and I am a stem cell biologist working at King’s College London in the Institute of Psychiatry, Psychology & Neuroscience. I am part of a research group that uses cellular and molecular biology, as well as bioinformatics, to further our understanding of psychiatric conditions such as autism and schizophrenia.
I am – funnily enough – also neurodivergent myself, with an immense fixation on asking the questions “why?” and “how?”, which is what brought me to science in the first place.
Here, I would like to share our newest research project, which aims to explore a potential link between schizophrenia and Amyotrophic Lateral Sclerosis (ALS) – two conditions which impact millions of people and their loved ones worldwide. By investigating this, we hope to not only gain understanding but also identify new ways they could be treated; and by writing this, I hope to answer all of your questions, starting with “How” and “Why”.
What is Schizophrenia?
Schizophrenia is a psychiatric condition impacting over 24 million people worldwide, which often presents with symptoms such as hallucinations, confusion, delusions, depressive tendencies, and feeling disconnected. It often manifests in young adults and children, and symptoms gradually become more intense.
While the causes of schizophrenia are not fully understood, risk factors include genetic predisposition, environmental factors, and substance abuse. While with treatment, such as medication and therapy, marked improvement is seen in about half of patients, the other half continue to face lifelong struggles.
What is ALS?
Amyotrophic lateral sclerosis (ALS), often referred to as motor neuron disease or Lou Gehrig's disease, is a neurodegenerative disease which manifests in the progressive degeneration of upper and lower motor neurons. Symptoms of ALS include weakness and stiffness of the extremities, as well as muscle spasms, cramps, and twitches.
ALS is terminal, with treatments focusing on management of symptoms. While it most often manifests in patients over 45, it progresses rapidly, with most patients succumbing to the disease within 30 months from diagnosis.
Causes of ALS are also not fully understood, but we know that about 10-15% of cases are familial. These cases can be identified via genetic testing; however, a variety of genes have been linked to the disease. The other 85-90% of cases are caused by a variety of environmental factors, viruses, and autoimmune processes.
The Connecting Key Player
While the two diseases differ in almost every aspect, including age of onset and presentation, epidemiological studies – studies focusing on the patterns and distribution of disease – have found that schizophrenia is reported at a higher rate within the families of ALS patients, suggesting the presence of a potential biological factor. Furthermore, previous genetic studies support a shared biological basis between ALS and neuropsychiatric disorders.
One of the genes linking the two conditions identified in prior studies is called Neurexin-1 (NRXN1). It is one of the biggest genes in the human genome, and it is responsible for the expression of a protein of the same name. The NRXN1 protein plays an important role in forming synapses, the connections between neurons that allow them to communicate with each other using electrical and chemical signals.
The NRXN1 gene can exist in multiple different forms, known as “isoforms.” These are different versions of the same gene that can affect how it is used by cells and how the resulting protein functions. Mutations in NRXN1 can change the balance between these isoforms, which may affect how neurons communicate with one another.
In mice, it has been found that such mutations lead to symptoms which resemble neurodegenerative conditions. In humans, people carrying these mutations often develop movement-related abnormalities resembling the symptoms of ALS.
Our Mission
Recent findings have identified changes within a region of NRXN1 that are strongly associated with ALS. Our group’s previous research has also established a link between this region and psychiatric conditions, including schizophrenia. We have also shown that it regulates both the physical structure (the morphology, a.k.a. physical appearance) and function of neurons.
Building on these findings, our brand-new research project, led by me and supported by my wonderful mentors Ahmad and Deepak as well as my colleagues, will investigate how mutations in this region of NRXN1 affect the behaviour of neurons.
Our experiments will range from growing neurons on chips and measuring their electrical activity to analysing valuable genetic data collected from patients and donors. By looking at this data, we hope to identify patterns in gene activity that may be linked to ALS and schizophrenia.
This project is particularly exciting because, for the first time, it will allow us to investigate how mutations in this important region of NRXN1 change the way neurons function. In doing so, we hope to gain new insights into the biological processes underlying both schizophrenia and ALS.
As much as I look forward to this research bringing us some answers and hopefully serving as a stepping stone towards better treatment options for patients and their families, what I look forward to most is the questions that will arise on the way. Because, at the end of it all, that’s what science is all about: asking the questions “why?” and “how?”.
