Neurodegenerative diseases

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 prolyl oligopeptidase.

Prolyl oligopeptidase

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. It has been found that PREP accelerates the accumulation of toxic protein aggregates, but the mechanism is not fully understood. Our laboratory focuses on studying PREP in more detail to reveal the exact mechanism by which the effects on protein aggregation occur. Additionally, we have found small molecule hit compounds which decrease accumulation of harmful proteins and enhance their natural clearance from affected tissues in cells and animal models. These effects are so prominent that we are seeking a commercial partner to help us in progressing these compounds towards human trials.

PREP pharmacology

PREP pharmacology focuses on finding how PREP increases protein accumulation and whether PREP inhibitors can block this. So far, we have found two separate mechanisms: PREP directly interacts with aggregation-prone proteins like α-synuclein and increases their aggregation and decreases cellular recycling mechanisms, which are called autophagy. Our studies aim to reveal the exact mechanism behind these phenomena in cellular and animal models.

Parkinson's disease

Lewy bodies are dense, harmful protein deposits which are a characteristic finding inside the brains of Parkinson's disease patients. One of the main constituents of Lewy bodies is aggregated α-synuclein. Additionally, α-synuclein forms aggregates independently from Lewy bodies. Small aggregates are called oligomers, while large, thread-like constructs are called fibrils. These aggregated forms of α-synuclein are harmful to cells by various mechanisms and can even translocate from one cell to another.

Our studies have shown that PREP directly interacts with α-synuclein. This interaction, which has been confirmed in cellular and animal models, increases the formation of toxic α-synuclein oligomers. This aggregation process may be decelerated by using PREP inhibitors to protect neurons from α-synuclein toxicity.

Alzheimer's disease

Two types of protein aggregates are found in Alzheimer's disease: amyloid beta forms aggregates outside the cells, while a protein called Tau aggregates inside the cells. Although amyloid beta has been the main target for Alzheimer's drug development in recent years, these new investigational therapies have not been very successful in clinical trials. Subsequently, attention has shifted towards Tau, which is now considered the main cause of neuronal death in Alzheimer's disease.

We have shown that PREP is found in close proximity to Tau in the brains of Alzheimer's disease patients. Therefore, it is highly possible that PREP has a similar interaction with Tau as it has with α-synuclein. One of our recent focuses is to test PREP inhibitors in Tau-based Alzheimer's disease models.

Autophagy and other mechanisms in neurodegeneration

Autophagy (meaning self-devouring, as derived from Ancient Greek) is a complicated mechanism by which cell recycles unwanted or unneeded proteins or other biological molecules. Under normal circumstances cells are able to dismantle any harmful structures that form in example due to failed protein folding. However, this process becomes less efficient during aging and is further impaired in Parkinson's and Alzheimer's diseases. Reduced autophagy is thought to be one of the mechanisms behind accumulation of α-synuclein, amyloid beta and Tau protein aggregates.

In 2014, we revealed that PREP reduces autophagy, an effect which may be reversed with PREP inhibitors to accelerate autophagy. Accelerated autophagy may benefit in several neurodegenerative diseases. Our more recent findings have connected PREP to other toxic mechanisms as well, such as oxidative stress.

PREP medicinal chemistry

Our medicinal chemistry efforts are led by Doc. Erik Wallén.

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. We believe that there is still more to be found in PREP and seek to find novel chemical compounds to target PREP and aid in neurodegenerative diseases.

These days we use synthetic organic chemistry and computer-assisted drug discovery methods to extend our knowledge on possible ways to manipulate PREP enzyme. The highly dynamic structure of PREP includes several moving loop structures and a large amount of possible configurations, some of which we suspect may be locked in place temporarily (or permanently) with small molecule compounds. As we are no longer targeting the enzymatic site of PREP, we call our compounds PREP ligands instead of traditional inhibitors.

We have made significant progress in finding good PREP ligands; significant enough that we are currently seeking partners to aid in lead selection and optimisation to take our ligands into human trials!