The Role of SLC13A5 in Neuronal Function

Citrate is a vital component for neuronal metabolism and development, with a membrane transport protein known as SLC13A5 playing a critical role in this process. This protein has been associated with a severe form of epileptic encephalopathy, which highlights the importance of understanding its function and structure.

Research Insights from Recent Projects

Recent research conducted by scientists at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences builds upon findings from the RESOLUTE and REsolution flagship projects. The study provides a comprehensive analysis of SLC13A5, examining 38 mutant variants and their implications for disease mechanisms.

Understanding Citrate's Importance

Citrate, which is the negatively charged ion derived from citric acid, serves as a key player in cellular metabolism. In the citric acid cycle, it aids in breaking down organic substances to generate chemical energy. Additionally, it produces precursors necessary for the biosynthesis of fatty acids and critical signaling molecules that are essential for inflammation and cell development.

In neurons, citrate acts as a neuromodulator, directly influencing neuronal activity. This is reflected in the high concentrations of citrate found in cerebrospinal fluid, leading to the expression of elevated levels of the SLC13A5 transporter, which facilitates citrate uptake.

Consequences of Impaired Transport

When the SLC13A5 transporter is dysfunctional, it can result in SLC13A5 Citrate Transporter Disorder, a severe epilepsy form linked to impaired brain development, scientifically termed developmental epileptic encephalopathy (DEE). The condition arises from mutations in the SLC13A5 gene, but the specific mutations and their effects on transporter function have remained largely unexplored.

Deep Mutational Scanning: A Key Research Method

To fill this knowledge gap, researchers utilized a technique known as deep mutational scanning (DMS) to analyze nearly 10,000 genetic mutations affecting the SLC13A5 protein's function. This extensive dataset was complemented by computational analyses focused on protein stability, leading to the selection of 38 mutant variants for further experimental investigation.

Findings on Disease Mechanisms

The study uncovered several molecular mechanisms associated with the disease, including variations in transporter production levels and their specific localization within the cell membrane, as well as the rate of citrate transport itself.

Through this research, scientists were able to identify and characterize variants of the SLC13A5 transporter that contribute to the disease. Additionally, computational analysis provided insights into protein stability across different conformations and established an evolutionary conservation score for all examined variants.

Implications for Future Research

The findings underscore the importance of systematically investigating the effects of genetic variants, especially in rare diseases like SLC13A5 citrate transporter deficiency. The research not only clarifies molecular disease mechanisms but also offers valuable insights into genetic diversity and its implications for human health.

Patient data for this study were generously provided by the TESS Research Foundation, an organization committed to advancing research on SLC13A5 citrate transporter deficiency.