Small RNAs: New Clues to Schizophrenia & Bipolar Disorder

For decades, the study of brain disorders has largely centered on proteins and the genes that create them. But emerging research suggests a more nuanced picture, one where compact regulatory molecules called small RNAs may play a surprisingly significant role in conditions like schizophrenia and bipolar disorder – and in the healthy brain itself. A new study from Thomas Jefferson University’s Computational Medicine Center is adding weight to this idea, uncovering complex patterns in these small RNAs that correlate with the presence and progression of these mental health conditions.

Uncovering the Hidden Language of the Brain

The research, published as a preprint in Translational Psychiatry, investigated small non-coding RNAs (sncRNAs) extracted from the prefrontal cortex of 93 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD), and compared them to a control group of 77 individuals. The study, led by S. Nersisyan and colleagues, didn’t simply look for the presence of these RNAs, but meticulously profiled their variations – known as isoforms – and how they change in people with these disorders. The team found that the vast majority of these sncRNAs fall into a few key categories: miRNA isoforms (60.6%), tRNA-derived fragments (17.8%), rRNA-derived fragments (11.4%), and Y RNA-derived fragments (8.3%).

Small RNAs are not directly involved in building proteins, but instead act as regulators, influencing which genes are turned on or off, and how strongly. Think of them as volume controls for gene expression. This research suggests that disruptions in these “volume controls” could be a key component of schizophrenia and bipolar disorder. In individuals with schizophrenia, the study identified significant changes in the abundance of 15% of all sncRNAs analyzed. While the changes in bipolar disorder were correlated with those seen in schizophrenia, they appeared less pronounced.

What are Small RNAs and Why Do They Matter?

To understand the significance of this research, it’s helpful to define what small RNAs are. These are short strands of RNA – a molecule similar to DNA – that don’t code for proteins. Instead, they have regulatory functions. MicroRNAs (miRNAs), for example, bind to messenger RNA (mRNA) molecules, which carry genetic instructions from DNA to the protein-building machinery of the cell. By binding to mRNA, miRNAs can prevent the production of certain proteins, effectively silencing specific genes. Other types of small RNAs, like tRNA-derived fragments (tRFs) and rRNA-derived fragments (rRFs), are as well emerging as key regulators of gene expression, though their precise roles are still being investigated.

The Jefferson University team also discovered that modifications to the ends of miRNA molecules – specifically, the addition of nucleotides – play a crucial role in determining how these RNAs function. These modifications appear to influence the extent of the changes observed in individuals with schizophrenia and bipolar disorder, independent of the underlying miRNA sequence.

Beyond Correlation: Linking Small RNAs to Brain Processes

The study didn’t stop at identifying changes in small RNA levels. Researchers also investigated how these changes relate to critical brain processes. By analyzing which genes are co-expressed with the altered small RNAs, they found strong links to synaptic signaling (communication between nerve cells), neurogenesis (the birth of new neurons), memory, behavior, and cognition – all processes known to be disrupted in schizophrenia and bipolar disorder. Interestingly, the researchers also observed patterns suggesting accelerated aging in the brains of individuals with these conditions, as reflected in the changes in small RNA profiles.

The Role of Jefferson’s Research and Ongoing Investigations

This research builds on earlier work at Thomas Jefferson University exploring the potential of small RNAs as biomarkers for mental illness. Previous studies have focused on identifying unique small RNA signatures that could help diagnose these conditions or predict treatment response. The current study expands on this work by providing a more comprehensive analysis of the types of small RNAs involved and their functional implications.

Alongside this work on psychiatric disorders, Thomas Jefferson University is also investigating the potential of a chatbot, RehaBot, to improve physical activity in patients with traumatic brain injury (TBI). This separate study, led by Amanda Rabinowitz and Tessa Hart, aims to address the increased risk of neurodegenerative diseases associated with TBI by promoting regular exercise. The program utilizes personalized goals and text message reminders to encourage sustained physical activity.

Limitations and Future Directions

It’s important to note that this research is still in its early stages. The study, being a preprint, has not yet undergone the rigorous peer review process that is standard for published scientific articles. The sample size, while substantial, is limited, and the findings may not be generalizable to all individuals with schizophrenia or bipolar disorder. The study also relied on post-mortem brain tissue, which may not fully reflect the dynamic changes occurring in the living brain. Correlation does not equal causation, and further research is needed to determine whether the observed changes in small RNAs are a cause or a consequence of these disorders.

Looking ahead, researchers plan to conduct larger studies with more diverse populations, and to investigate the potential of targeting small RNAs as a therapeutic strategy for schizophrenia and bipolar disorder. This could involve developing drugs that modulate the levels of specific small RNAs, or that correct the modifications that disrupt their function. The team also intends to use wearable technology, such as smartwatches, to monitor the impact of interventions aimed at improving brain health.

The ongoing research at Thomas Jefferson University, and elsewhere, is slowly but surely unraveling the complex molecular mechanisms underlying mental illness. While a complete understanding remains elusive, the emerging role of small RNAs offers a promising new avenue for diagnosis, treatment, and prevention.