Project Details
Projekt
Calpains as a therapeutic target in polyglutamine disorders
Subject Area
Molecular and Cellular Neurology and Neuropathology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 421785405
Polyglutamine disorders represent a group of nine neurodegenerative proteinopathies which result from a single mutation, a CAG repeat expansion in the disease-associated gene, and the thereby caused pathological elongation of a polyglutamine region in the encoded protein. Although these diseases can vary strongly in their clinical picture, they share many similarities at the molecular level, which could serve as a starting point for therapeutic approaches. A characteristic of polyglutamine disorders is the occurrence of toxic and aggregation-prone disease protein fragments, which are known to be generated by proteases such as the apoptosis-mediating caspases or the calcium-activated, regulatory calpains. In two of our earlier preclinical studies, we demonstrated that calpains are overactivated in mouse and rat models of Huntington disease, and that the administration of the experimental drug olesoxime, a mitochondria-targeting cholesterol derivative, revealed phenotype-attenuating properties by lowering calpain activation and reducing the herewith associated huntingtin proteolysis. Despite clear results, the role of calpains in other polyglutamine disorders and the precise mode of action of olesoxime remain obscure. For this reason, we aim to analyze the role of calpains in two other polyglutamine diseases, the spinocerebellar ataxias type 3 and type 17, and to investigate the exact molecular mode of action of olesoxime. This will include investigations of the calpain system in various animal models of these diseases, as well as the study of the effects of olesoxime on mitochondria and neuronal calcium homeostasis, using cell lines and IPS-derived neurons of patients. The results of this proposed study will allow us to further explore the exact role of calpains in polyglutamine diseases as well as other neurodegenerative pathologies, and to evaluate olesoxime as a potential therapeutic for these disorders.
DFG Programme
Research Grants
