Project Details
Projekt
Development of Selective Caspase-2 Inhibitors for the Treatment of Neurodegenerative Diseases
Applicant
Privatdozent Dr. Steffen Pockes
Subject Area
Pharmacy
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
from 2020 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436921318
Our goal is to repair synaptic transmission in tauopathies by selectively inhibiting caspase-2 (Casp2). Lowered Casp2 levels or genetically deleting of Casp2 protects neurons from excitotoxicity, oxidative stress and glaucoma. In addition, synaptic and cognitive deficits caused by transgenic expression of mutant Huntingtin, Tau and APP (triggering Huntington's disease, frontotemporal dementia and Alzheimer's disease) are prevented. The cytoskeletal protein Tau is the only known substrate of Casp2 in the brain. Casp2 cleavage of tau at Asp-314 produces the cleavage product Δtau314 and leads to synaptic dysfunction and impaired cognition by allowing tau to accumulate in dendritic spines and reduce AMPA receptors in the postsynaptic membrane. This significantly disrupts neuronal communication at the synapses. Furthermore, it has also been found that Δtau314 is elevated 3-fold in the brains of Alzheimer's patients. Based on these and other findings, our overarching hypothesis is that preventing Casp2 from cleaving tau preserves cognitive functions in tauopathies. So far, the vast majority of in vivo studies have shown that Casp2 expression levels regulate neurodegeneration. Nevertheless, it has not yet been demonstrated that the proteolytic activity of Casp2 is directly involved. The expression level and the activity of the proteases are usually linked. However, Casp2 is unusual in that it has both catalytic and non-catalytic functions. We are convinced that the proteolytic activity of Casp2 is responsible for neurodegenerative anomalies, which urgently require high-quality and selective Casp2 inhibitors for use as pharmacological in vivo tools ("Casp2 probes"). These tools are specifically used to validate targets in preclinical studies to demonstrate - in this case - that inhibition of Casp2 activity can prevent neurodegenerative abnormalities. However, since no Casp2 probes are available, the characterization of this enzyme in tauopathies is incomplete and its role is not yet sufficiently understood. For this reason, we are trying to develop new selective Casp2 inhibitors based on the structural findings of the cleavage product Δtau314. With these results, the molecules are to be further developed via peptidomimetics into small molecule drugs in order to meet the requirements of a well bioavailable and CNS-penetrating drug. To achieve this goal, numerous pharmacological (in vitro & in vivo) and pharmacokinetic investigations are necessary in addition to the chemical production of the compounds.
DFG Programme
Research Fellowships
International Connection
USA
