In a groundbreaking study, scientists have uncovered new insights into the role of a faulty brain protein, SLC13A5, in triggering a severe form of epilepsy. This discovery, published in Science Advances, builds on data from the RESOLUTE and REsolution flagship projects, shedding light on the mechanisms of SLC13A5 Citrate Transporter Disorder, a condition linked to developmental epileptic encephalopathy (DEE).
The research was conducted by a team at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. They investigated 38 mutant variants of the SLC13A5 protein, crucial for citrate metabolism in neurons. Citrate, the ion of citric acid, plays a pivotal role in cellular metabolism and neuronal activity, and its uptake is facilitated by the SLC13A5 transporter.
Understanding the Role of Citrate in Neuronal Function
Citrate is central to the citric acid cycle, often described as the “hub” of cellular metabolism. It is involved in breaking down organic substances to generate energy and produce precursors for fatty acids and signaling molecules. In neurons, citrate acts as a “neuromodulator,” influencing neuronal activity and maintaining high concentrations in cerebrospinal fluid.
However, when the SLC13A5 transporter is dysfunctional due to genetic mutations, it leads to SLC13A5 Citrate Transporter Disorder. This severe epilepsy variant is characterized by impaired brain development, a condition known as developmental epileptic encephalopathy.
Breakthrough Research Using Deep Mutational Scanning
To address the knowledge gap surrounding SLC13A5 mutations, the researchers employed “deep mutational scanning” (DMS). This technique allowed them to analyze the effects of nearly ten thousand genetic mutations on the transporter’s function. The study was further enriched by computational analyses of protein stability, identifying 38 critical mutated variants for experimental investigation.
“With these results, we were able to identify and characterize disease-causing variants of the SLC13A5 transporter,” explains co-first author Wen-An Wang.
The findings revealed several molecular mechanisms linked to the disease’s manifestation, including variations in transporter production levels, their localization in the cell membrane, and the citrate transport rate. These insights are crucial for understanding how specific mutations contribute to the disorder.
Implications for Understanding Genetic Diversity and Health
Co-first author Evandro Ferrada, now at the University of Valparaíso in Chile, highlighted the importance of computationally analyzing mutant variants to assess protein stability and establish an evolutionary conservation score for all variants. This approach not only aids in understanding rare diseases like SLC13A5 deficiency but also provides insights into genetic diversity’s impact on human health.
“Our work highlights the importance of systematically investigating the effects of genetic variants,” emphasizes senior author Giulio Superti-Furga. “This approach helps us uncover molecular disease mechanisms and gain insights into the impact of variants in the general population.”
The study was supported by the REsolution consortium, a successor to the RESOLUTE project, which mapped the entire SLC transporter family. Patient data was provided by the TESS Research Foundation, dedicated to advancing research on SLC13A5 citrate transporter deficiency.
Looking Forward: Future Research and Potential Therapies
The findings from this study lay the groundwork for future research into epilepsy and related neurological disorders. By understanding the molecular mechanisms at play, researchers can develop targeted therapies to address the underlying causes of these conditions.
As the scientific community continues to explore the complexities of genetic mutations and their effects, this research represents a significant step forward in the quest to better understand and treat severe forms of epilepsy. The implications extend beyond rare diseases, offering valuable insights into genetic diversity and its broader impact on human health.
With continued support from research foundations and collaborations across scientific disciplines, the potential for breakthroughs in treating and managing neurological disorders remains promising. The work of the CeMM team and their partners serves as a testament to the power of innovative research in unraveling the mysteries of the human brain.
