Researchers decipher the function of an ion channel involved in cellular degradation processes and create new possibilities for Parkinson’s therapies.

Washbowls, bathtubs, and sinks are all fitted with overflows to stop water from sloshing over the edge. Such a safety mechanism also exists in the recycling centers of human cells. This was revealed in a new study by researchers from Bonn-Rhein-Sieg University of Applied Sciences (H-BRS), LMU Munich, TU Darmstadt, and the company Nanion Technologies, which has been published in the journal PNAS (Proceedings of the National Academy of Sciences). Led by pharmacologist Professor Christian Grimm (LMU Munich) and Dr. Oliver Rauh (H-BRS), the scientists have deciphered the mechanism of the ion channel TMEM175, which had been subject to much debate, and showed: In lysosomes, the ion channel seemingly carries out the role of an overflow valve, preventing excessive acidification.

Fine-tuning of acidity in lysosomes
Lysosomes are small, membrane-enclosed vesicles which perform the function of recycling centers in human cells – that is to say, they break down macromolecules into their basic components. A prerequisite for this is an acidic pH. In essence, pH quantifies the concentration of protons (H⁺) in an aqueous solution. As a rule, the lower the pH value, the higher the proton concentration. So that the interior of lysosomes remains acidic, a transmembrane protein pumps protons into the lysosomes. However, the fine-tuning of the pH is dependent on further proteins, which are located in the lysosomal membrane. The paper published in PNAS shows the decisive role of TMEM175 here.

The researchers speculate that the valve function of TMEM175 in healthy cells ensures an optimally acidic pH and thus facilitates the smooth operation of lysosomal degradation processes. Patients who carry a mutation in this ion channel, by contrast, experience a loss of pH regulation. This inhibits the degradation processes of proteins in the lysosome, which can lead in turn to neuronal cell death. Numerous research papers in recent years have shown that disorders of the lysosomal degradation function are involved in the process of aging and the development of neurodegenerative diseases like Parkinson’s. “Our study establishes that the ion channel TMEM175 plays a decisive role here,” says Dr. Oliver Rauh.

Channel protein TMEM175 conducts potassium ions and protons
Regarding the background: The cellular localization and function of the ion channel TMEM175 was long unknown, a fact reflected in its unassuming name: TMEM175 simply stands for transmembrane protein 175. In recent years, it increasingly became the focus of research attention, as its role in the emergence of various neurodegenerative diseases, especially Parkinson’s, gradually became apparent. In the meantime, several investigations have established without doubt that TMEM175 is a channel protein that conducts ions through the membrane of lysosomes. However, researchers disagreed on whether this channel primarily conducts potassium ions or protons, and what function the corresponding ion flows have in the lysosomes of healthy and sick cells.

Specific pH sensor in interior of lysosome
“I’ve worked on many ion channels, and TMEM175 is by far the strangest of them all,” says Dr. Oliver Rauh, who moved from TU Darmstadt to H-BRS to work in the research collaboration CytoTransport. “When we started on the project around six years ago, it was assumed that TMEM175 was a potassium channel. Its function was completely unknown. We’ve now been able to demonstrate that TMEM175 not only conducts potassium ions, but also protons, and is thus directly involved in the regulation of pH – that is, the proton concentration – in the interior of lysosomes.”

“Most of the experiments were conducted using the patch clamp method”, explains Christian Grimm, expert for the lysosomal patch clamp technique, which allows the electrophysiological characterization of ion channels in lysosome membranes. In this way, the researchers showed that TMEM175 is able to recognize the critical pH status and adapt the flow of protons through the ion channel accordingly.

“Our findings create an important foundation for a better understanding of functional processes in lysosomes and the function of the TMEM175 channel, which was contested before now”, say the authors. “At the same time, our insights into the protein TMEM175 offer a promising target structure for the development of drugs to treat or prevent neurodegenerative diseases like Parkinson’s.”