Ion channel as possible target structure for therapies

Lysosomal storage diseases are inherited disorders of the metabolism. They originate in various dysfunctions of lysosomes. With the aid of enzymes, these organelles break down components from their own cell as well as from other cells. Disease-causing genetic mutations lead to defects in enzymes or to membrane structures of the lysosomes. As a consequence, there is a build-up of biological macromolecules – initially in cells but spreading later throughout the organism. This results in lysosomal storage diseases with neurodegenerative symptoms, which typically begin in early childhood and go along with greatly reduced life expectancy and quality of life.

LMU pharmacologist Prof. Christian Grimm from the Walther Straub Institute of Pharmacology and Toxicology, working in cooperation with Prof. Dominik Paquet(Institute for Stroke and Dementia Research, University Hospital, LMU Munich) and other researchers, has now managed to modulate a specific cation channel in lysosomes. In a mouse model and in human nerve cells grown in the laboratory, this modulation ameliorated typical symptoms of three neurodegenerative diseases. In the view of the researchers, the ion channel could be a target for future therapies.

An ion channel as key structure of lysosomal storage diseases

It has been known for some time that calcium ions regulate numerous lysosomal processes. “In the case of one of the diseases, mucolipidosis type IV, we already know of a direct connection between impaired lysosomal calcium release and neurodegeneration caused by dysfunction of the lysosomal cation channel TRPML1,” says Grimm. Defects of TRPML1-mediated calcium release also play a role in other diseases such as Niemann-Pick type C1, Niemann-Pick type A, and Fabry disease.

While the ion channel TRPML1 has been the object of many research projects, continues Grimm, the consequences of modulation of the related two-pore channel TPC2 have been largely unknown to date. “We hypothesized that TPC2 activation could modulate the lysosomal calcium signal transmission, particularly in the case of lysosomal storage diseases in which TRPML1 is mutated,” says the LMU scientist. Together with colleagues, he investigated Batten disease, mucolipidosis type IV (MLIV), and Niemann-Pick disease type C. For all three diseases, it had already been established that they are associated with impaired lysosomal calcium signal transmission and TRPML1 dysfunction.

The researchers discovered that activation of TPC2 with small molecules led to an amelioration of lysosomal diseases manifestations. This was revealed by electron microscopy based on a lower accumulation of cellular metabolic products. The team of researchers investigated TPC2 activation in skin cells of patients with mucolipidosis type IV, Niemann-Pick type C1, or Batten disease. In collaboration with Dominik Paquet, they also investigated TPC2 activation directly in human neurons created from stem cells. “To demonstrate the concept in vivo, we tested the activation of TPC2 in an MLIV mouse model,” says the LMU pharmacologist. This also confirmed the hypothesis.

Grimm’s summary: “Overall, our data indicates that TPC2 is a highly promising target for the treatment of various lysosomal storage diseases.” He hopes that “activation of TPC2 has the potential for novel therapies, particularly for the treatment of lysosomal storage diseases with impaired calcium metabolism.”

Anna Scotto Rosato, Einar K Krogsaeter, Dawid Jaślan, Carla Abrahamian, Sandro Montefusco, Chiara Soldati, Barbara Spix, Maria Teresa Pizzo, Giuseppina Grieco, Julia Böck, Amanda Wyatt, Daniela Würkhaus, Marcel Passon, Marc Stieglitz, Marco Keller, Guido Hermey, Sandra Markmann, Doris Gruber-Schoffnegger, Susan Cotman, Ludger Johannes, Dennis Crusius, Ulrich Boehm, Christian Wahl-Schott, Martin Biel, Franz Bracher, Elvira De Leonibus, Elena Polishchuk, Diego L Medina, Dominik Paquet & Christian Grimm. TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann–Pick type C1, and Batten disease. EMBO Mol Med, 2022.