Neuronal ceroid lipofuscinosis (NCL) is the commonest form of juvenile dementia, affecting some 70,000 children worldwide. Around 700 cases of the disease are known in Germany. The condition is caused by genetic mutations. Victims first lose their sight, and this is followed by the progressive – and ultimately fatal – deterioration of vital cognitive and motor functions. There is currently no effective treatment for the disease. The mutations responsible for the disorder result in metabolic defects that disrupt the function of the cellular organelles known as lysosomes. Lysosomes – intracellular, membrane-bounded vesicles – are among the tiniest of all cell organelles, which makes them exceedingly difficult to study. LMU pharmacologist Christian Grimm is one of Europe’s leading specialists in the metabolism and functions of lysosomes, and uses a technique known as patch clamping to study the transport of ions across the lysosomal membrane. In his latest project, entitled “Novel Therapeutic Strategies for Rare Diseases with Endolysosomal Dysfunction” and conceived in collaboration with neurobiologist Dominik Paquet of the Institute for Stroke and Dementia Research, he wants to explore ways of restoring normal ionic conditions within defective lysosomes, and identify new drug targets for the treatment of NCL and other metabolic diseases of lysosomes. The NCL Foundation, a charity based in Hamburg, will provide approximately 86,000 euros for the project.
Since the primary function of lysosomes is waste disposal, they contain digestive enzymes. These enzymes work properly only if the concentrations of various electrically charged atoms and molecules (‘ions’) are in the appropriate range. Proteins called ion channels control the passage of ions across the vesicle membrane, and therefore play an essential role in maintaining lysosomal function. The aim of the new project is to determine whether these proteins could serve as drug targets for the development of an effective treatment for NCL. “Using the patch-clamping method, we can control the function of individual ion channels, and it might be possible to find ways of selectively altering their transport properties, in such a way that the correct ion concentration within the vesicle is restored,” Grimm explains. Moreover, the lysosomal system plays a significant role not only in NCL, but also in many other debilitating disorders, including dementias in the elderly. With regard to the latter, in the majority of patients, no clear-cut genetic mutations can be directly associated with the disease. However, certain rare forms of senile dementia have been causally linked to mutations in single genes. These insights explain why, in addition to NCL, the project will also look at cell-based models of senile dementia. More specifically, Dominik Paquet plans to use the CRISPR/Cas technology to introduce specific genetic mutations into the genomes of pluripotent stem cells, and then induce these cells to generate neurons and other types of brain cells in culture. This will allow him to characterize the impact of the introduced mutations on these differentiated cell types, and enable him to test the effects of modulators of various endolysosomal ion channels on the genetically altered phenotypes.
The goal of the NCL Foundation is to stimulate research on NCL by providing financial support for innovative and promising projects. The grant approved for the new project includes funding for a doctoral student.