Neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, affect the brains and other tissues of patients. The death of neuronal cells inside the brains and other tissues causes several problems for the patient. Common symptoms of neurodegenerative diseases include, among others, memory loss and movement disorders. While the exact causes of these diseases are currently unknown, one common factor between them is the accumulation of toxic protein deposits: α-synuclein in Parkinson's disease and amyloid beta and Tau proteins in Alzheimer's disease.
There is no known cure for these progressive diseases. Current treatments may help in alleviating some of the symptoms, but eventually these diseases lead to early loss of life of the affected individuals. As the general population of the world gets progressively older, the need for effective treatments for neurodegenerative diseases keep increasing, as these diseases occur most commonly in the elderly. We seek to tackle the problem of neurodegenerative diseases by targeting protein phosphatase 2A (PP2A).
PP2A is important regulator for the cell functions, and several studies indicate that PP2A activity has been lowered in the neurodegenerative diseases. What makes PP2A very tempting target for drug discovery, is that it regulates several mechanisms related to neuronal death - protein stability and accumulation, protein processing and neuronal inflammation. PP2A activation has been shown to have beneficial effects in various models for neurodegenerative diseases but it's complicated structure and functions make it also a difficult target. However, we have two pathways how we aim to target PP2A - prolyl oligopeptidase and MID1.
NeuroCure pharmacology focuses on finding the mechanisms how PREP and MID1 regulate PP2A and affect the mechanisms of neurodegenerative diseases, and how small molecular ligands targeting on PREP and MID1 re-activate PP2A and have impact in the models of neurodegenerative diseases.
Prolyl oligopeptidase (PREP, also called POP or PEP) is a serine protease enzyme, which is mostly located in the brain, but also in other tissues. There has been several indications and earlier studies since 1980s that PREP would have a role in neurodegeneration but the mechanisms have remained unclear. Our laboratory has focused for more than 10 years on studying PREP to reveal the mechanisms how PREP contributes to the neurodegenerative diseases.
PREP studies have mostly focused on its enzymatic cleavage but we have found that PREP forms protein-protein interactions. These interactions include alpha-synuclein and Tau, aggregating proteins in Parkinson's and Alzheimer's disease, respectively, and PP2A. PREP enhances the aggregation of alpha-synuclein and Tau, and inactivates PP2A. Our studies have shown that small-molecular ligands can regulate these interactions, leading to several beneficial effects in the neurodegenerative disease models. One the latest findings in the PREP project was that we discovered novel binding pocket in the PREP, leading to completely novel PREP ligand series. PREP small molecule project is now taken further by
MID1 (Midline1) protein is our novel project. MID1 is responsible for transporting PP2A for degradation, and our project focuses on interfering this process. This mechanism leads to elevated PP2A levels and activity, and studies have shown that unspecific MID1 regulators have beneficial impact particularly in the Alzheimer's disease models. However, we aim to discover completely novel and specific MID1 ligands that can be used to activate PP2A.
Our medicinal chemistry efforts are led by Dr. Erik Wallén (docent).
From 1980s to 2000s there was great effort from several entities to find inhibitors of PREP, as inhibiting the enzyme was implied to have potential memory-enhancing effects. These efforts ended at the turn of the century with potent inhibitors of PREP enzymatic activity failing in phase II clinical trials. We suspect that the failures were due to wrong hypotheses and while no marketable drugs came out of the trials, it was found that PREP inhibition is safe and tolerable. Our recent findings in protein-protein-interactions of PREP revealed also novel binding pocket, and this allowed us to synthesize completely novel PREP ligands. These ligands are now in further development in
Novel target, MID1, is very interesting target for medicinal chemistry, and we collaborate closely with modelling and structural chemistry to develop novel and effective MID1 ligands to battle neurodegenerative diseases.