Lili Bako

Psychiatric and neurodegenerative disorders differ in age of onset, symptoms, and the parts of the body they affect. However, emerging research suggests an overlap between the biological mechanisms that drive these disorders. 

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterised by the progressive degeneration of upper and lower motor neurons, leading to muscle weakness, paralysis and respiratory failure. Although ALS is primarily recognised as a motor neuron disease, cognitive impairments are also common. Studies have also found higher rates of schizophrenia reported among relatives of people with ALS, suggesting these conditions may share common biological mechanisms. 

Schizophrenia is thought to be driven by changes in the form and function of neurons within the brain. Multiple studies suggest that alterations in the function of synapses, the point at which communication between neurons occurs, are a primary site affected in this disorder. Large genetic studies are now providing us with a clearer understanding of the potential biological factors that contribute to these disorders. These studies have also revealed that there is an overlap in the genetic factors between ALS and schizophrenia, which may indicate a shared biological basis between these two disorders. 

Among these genes implicated is Neurexin-1 (NRXN1). NRXN1 has been strongly associated with psychiatric conditions, including schizophrenia, and is also emerging as being linked with ALS. People who carry NRXN1 variants (mutations or deletions) often experience motor difficulties, including delayed motor development and low muscle tone. 

Variants in NRXN1 can alter how the gene functions and have been linked to changes in the structure and activity of neurons and synapses. Recent findings from our group have identified specific variants in NRXN1, known to be linked with schizophrenia and psychiatric conditions, that also appear to be associated with ALS. However, it is still unclear how these variants affect nerve cell function and whether they contribute to the biological changes underlying schizophrenia or ALS.

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In this study, we will investigate whether specific NRXN1 variants contribute to both ALS and schizophrenia. First, we will analyse large genetic datasets from people with ALS to identify which NRXN1 variants are associated with the disease, and which types of nerve cells relevant for ALS could be affected.

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We will then use human stem cell models carrying a clinically relevant NRXN1 variant to study how alterations in this gene affect different types of neurons. Specifically, we will examine cortical glutamatergic neurons, which are important in psychiatric disorders, and lower motor neurons, which are selectively affected in ALS. By comparing cells carrying the NRXN1 variant with unaffected cells, we aim to understand how changes in this gene influence the structure and function of these neurons. 

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By combining laboratory experiments with analysis of genetic data, this project will generate novel insights into how NRXN1 affects these nerve cells. This work will help us better understand the biological links between ALS and schizophrenia and may reveal new insights into how these conditions develop. 

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