Two studies in Jülich shed light on structural changes in the protein DISC1 and point to a novel therapeutic approach
25 June 2025
Researchers at Forschungszentrum Jülich in Germany have published two new studies offering fresh insight into a protein believed to play a pivotal role in the development of chronic mental health conditions such as schizophrenia. The protein, known as DISC1, short for Disrupted in Schizophrenia 1 acts as a molecular scaffold in the healthy brain. It enables other proteins to perform essential tasks like cell division and neural development. But when its structure is compromised, DISC1 can no longer perform this key function with potentially serious consequences for the development of neurons or the nervous system.
Protein Aggregation as a Risk Factor
In the following study published in the Journal of Structural Biology: X, the Jülich team led by Dr Abhishek Arun Cukkemane from the Institute of Biological Information Processing - Structural Biochemistry, showed that mutations in a partially flexible section of DISC1, called the C-region can result in misfolding and aggregation. While this structural flexibility normally allows DISC1 to interact with a wide range of molecular partners, it also renders the protein vulnerable to conformational errors. As a result, it can form fibre-like clumps resembling tangled threads, which interfere with normal cellular processes, especially during the early neurodevelopment.
These misfolded aggregates have been identified as a potential risk factor for psychiatric conditions such as schizophrenia, bipolar disorder and major depressive disorder. The team was able to characterise the aggregation process in detail for the first time, using a combination of biophysical, biochemical and structural biology techniques.
These findings contribute to a deeper understanding of the biological underpinnings of psychiatric illness and provide important clues on how such conditions emerge, thus, laying the groundwork for more targeted and personalized approaches to diagnostic and therapeutic strategies in the future.
Potential of Tailored Therapeutics
Building on this, a second study by Dr Cukkemane - published in the European Journal of Pharmaceutical Sciences - presents a promising therapeutic avenue. The researchers developed peptide mimetics: small, custom-designed molecules that replicate the essential features of naturally binding peptides, allowing them to interact with biological targets like DISC1 and produce the same biological effect. In laboratory tests, these compounds were able to prevent the pathological aggregation of the protein, thereby preserving its normal function. The drug candidates were developed at Forschungszentrum Jülich and have since been patented.
For the first time, this points to a treatment strategy that targets the underlying molecular cause of certain mental health conditions, rather than merely addressing their symptoms.
"DISC1 is a key regulator of brain development," explains Dr Abhishek Cukkemane, lead author of both studies. "When its structure is altered, it disrupts the delicate balance of protein interactions essential to healthy brain function. Our work not only reveals how this pathological transformation occurs, but also outlines a concrete strategy to counteract it."
Towards New Therapies - and a Better Understanding of Mental Illness
The next phase of the research will focus on testing the peptide-based compounds in cell cultures and, subsequently, in animal models to assess their safety and effectiveness. The long-term aim is to advance these findings towards clinical trials and develop a new generation of treatments that tackle mental illness at its roots.
While clinical application is still some way off, one thing is already clear: these results offer a compelling biological explanation for conditions that have long eluded mechanistic understanding - and in doing so, mark an important step towards the destigmatisation of psychiatric disorders.
Contact Person
- Institute of Biological Information Processing (IBI)
- Structural Biochemistry (IBI-7)
