Utilizing Solid Supported Electrophysiology (SSME) to accelerate discovery of TRPML1 modulators

Neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease remain conditions with major unmet clinical needs. Abnormalities in the endosomal-autophagic-lysosomal system, progressive neurological dysfunction and regional neuronal loss constitute their common characteristics. Transient receptor potential mucolipin 1 (TRPML1) is a well-known, non-selective cation channel of the endolysosomal system that can transport Ca²⁺, Fe²⁺ and Zn²⁺. There is a strong connection between endolysosomal TRPML1 dysfunction and neurodegenerative disorders, thought to be a result of its importance in controlling calcium signalling and homeostasis of lysosomes, autophagy, and modulation of oxidative stress. Therefore, modulation of TRPML1 presents a promising strategy to improve the function of neurons impacted by neurodegenerative disorders by increasing autophagy and promoting the clearance of protein aggregates and reactive oxygen species (ROS) build-up.

Numerous platforms offer insights into TRPML1 function and pharmacology, however, lack of specific tools allowing for investigation of TRPML1’s role in pathological processes are still obstacles for drug discovery. Solid Supported Membrane Electrophysiology (SSME) present a novel high throughput method to resolve this challenge. Using enriched lysosomal fractions from recombinant HEK cell lines expressing TRMPL1 we have successfully developed SSME assays, using both SURFE²R N1 (single sensor) and SURFE²R 96SE platforms to investigate TRPML1’s cation selectivity and pharmacology. Both platforms show excellent reproducibility and platform-to-platform correlation.

SSME allows investigation of TRPML1 activity and response to drugs in its native environment without the need for continuous cell culture. In conjunction with other technologies, SSME technology facilitates reliable high- throughput compound screening, enabling discovery of novel TRPML1 modulators and aiding the advancement of knowledge of TRPML1 and its role in normal physiology and disease.