Parkinson: Ionenkanal als vielversprechender Ansatz für Wirkstoffe

All sinks, bathtubs, and kitchen sinks are equipped with an overflow drain that prevents water from spilling over the edge of the basin. A similar safety mechanism also exists in the recycling centers of human cells. This is shown by a new study conducted by researchers at Bonn-Rhein-Sieg University of Applied Sciences (H-BRS), LMU Munich, TU Darmstadt, and the company Nanion Technologies, which has now been published in the journal PNAS. The scientists led by pharmacologist Professor Christian Grimm (LMU Munich) and Dr. Oliver Rauh (H-BRS) have deciphered the previously controversial mechanism of the TMEM175 ion channel and demonstrate that, within lysosomes, the ion channel likely acts as an overflow valve that prevents excessive acidification.

Fine-tuning of the acidic pH in lysosomes

Lysosomes are small, membrane-bound vesicles that act as recycling centers in human cells—meaning they break down macromolecules into their basic building blocks. This process requires an acidic pH. The pH value is simply a measure of the concentration of protons (H+) in an aqueous solution. The rule is: the lower the pH value, the higher the proton concentration. To keep the interior of the lysosomes acidic, a transmembrane protein pumps protons into the lysosomes. However, the fine-tuning of the pH depends on other proteins located in the lysosomal membrane. The study published in PNAS now demonstrates the crucial role of TMEM175 in this process.

The researchers suspect that the valve function of TMEM175 in healthy cells maintains an optimal acidic pH level, thereby enabling lysosomal degradation processes to proceed smoothly. In contrast, patients carrying a mutation in this ion channel experience a loss of pH regulation. This inhibits protein degradation processes in the lysosome, which in turn can lead to the death of nerve cells. Numerous studies in recent years have shown that disruptions in lysosomal degradation are involved in the aging process and the development of neurodegenerative diseases such as Parkinson’s. “Our study provides evidence that the TMEM175 ion channel plays a crucial role in this process,” says Dr. Oliver Rauh.

The channel protein TMEM175 transports potassium ions and protons

Background: The cellular localization and function of the TMEM175 ion channel were unknown for a long time, a fact reflected in its rather uninformative name: TMEM175 simply stands for transmembrane protein 175. In recent years, it has increasingly become the focus of research as its role in the onset of various neurodegenerative diseases—particularly Parkinson’s disease—became clear. Several studies have now unequivocally demonstrated that TMEM175 is a channel protein that transports ions across the lysosomal membrane. However, researchers were divided on whether this channel primarily transports potassium ions or protons, and what function these ion fluxes serve in the lysosomes of healthy and diseased cells.

Specific pH sensor inside the lysosome

“I’ve worked on many ion channels, but TMEM175 is by far the strangest of them all,” says Dr. Oliver Rauh, who moved from TU Darmstadt to H-BRS to work on the DFG research network “Cytotransport.” “When we started the project in Darmstadt about six years ago, it was assumed that TMEM175 was a potassium channel. Its function was completely unknown. We have now been able to show that TMEM175 conducts not only potassium ions but also protons, and is thus directly involved in regulating the pH—that is, the proton concentration—inside lysosomes.”

“Most of the experiments were conducted using the patch-clamp technique,” explains Christian Grimm, an expert in lysosomal patch-clamp technology, which allows for the electrophysiological characterization of ion channels in lysosomal membranes. In this way, the researchers demonstrated that TMEM175 can detect the critical acidity status and adjust the proton flux through the ion channel accordingly

“Our findings provide an important foundation for a better understanding of functional processes in lysosomes and the role of the TMEM175 channel, which has been a subject of debate until now,” the authors state. “At the same time, they identify the TMEM175 protein as a promising target for the development of drugs to treat or prevent neurodegenerative diseases such as Parkinson’s.”

T. Schulze et al.: Proton-selective conductance and gating of the lysosomal cation channel TMEM175. PNAS 2025