Neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are progressive diseases where neuronal death in brain causes clinical symptons like memory loss or movement disorders. Current drug therapies cannot stop or even delay neurodegeneration, and this leads to more and more severe symptoms as the disease progressess. It is not known what causes neuronal death in the first place but common toxic factor for several neurodegenerative diseases is abnormal protein accumulation that harms neurons in several ways.

Our studies have revealed that prolyl oligopeptidase, PREP, is one factor to induce protein accumulation, and importantly, this can be blocked by small-molecule PREP inhibitors. Our research is focused on understanding the mechanisms of how PREP increases the accumulation of protein accumulation - particularly alpha-synuclein and Tau, and studying if PREP inhibitors are effective in preventing the aggregation-prone protein accumulation and dissolve the surplus of protein aggregates from cells via enhanced autophagy. Another important aim is to find the best PREP inhibitor compounds to stop neurodegenerative diseases.

PREP pharmacology focuses on finding the mechanisms how PREP increases protein accumulation and if PREP inhibitors can block this. So far, we have found two separate mechanisms - PREP interacts directly with aggregating proteins like alpha-synuclein and increases its aggregation, and it also decreases cellular recycling mechanisms, autophagy. In our studies, we aim to reveal the mechanisms from protein level to animal models.

Parkinson's disease

Alpha-synuclein aggregation forms Lewy bodies that are used as a disease hallmark in Parkinson's disease. Several studies have shown that alpha-synuclein aggregates - oligomers and fibrils - damage cells with various mechanisms and they can move from cell to cell, leading to disease progression. Our studies have shown that PREP interacts directly with alpha-synuclein and increases its aggregation and formation of toxic oligomers in cells and in animals.  By using PREP inhibitors, we can reduce synuclein aggregation process, and protect neurons from alpha-synuclein toxicity.

Alzheimer's disease

In Alzheimer's disease, amyloid-beta forms aggregates outside the cells but protein called Tau aggregates inside the cells. Although amyloid-beta has been the main target for drug development, therapies targeting this have not been very succesfull in clinical trials. It has raised the interest in Tau that is now considered the main cause for neuronal death in Alzheimer's disease. We have shown that PREP is in close proximity with Tau in Alzheimer's disease brain and therefore, it is highly possible that PREP acts similarly with Tau as with alpha-synuclein. One of our recent focuses is to test PREP inhibitors on Tau-based Alzheimer's disease models.

Autophagy and other mechanisms in neurodegeneration

Autophagy is cell's own recycle center and it takes care of protein aggregates - normally. However, in aging and in Alzheimer's and Parkinson's disease, autophagy is impaired that increase protein accumulation and toxicity. In 2014, we revealed that PREP reduces autophagy and PREP inhibitors can accelerate autophagy, leading to decreased protein accumulation. This can be very beneficial in several neurodegenerative diseases, and our recent findings have connected PREP to other toxic mechanisms as well, such as oxidative stress.

PREP wouldn't be a drug target without medicinal chemistry and small-molecule inhibitors. Therefore, we have a medicinal chemistry section, led by Dr. Erik Wallen, that focuses on developing novel PREP inhibitors. There was a wide drug discovery on PREP and PREP inhibitors on 1980-2000 and several hundred PREP inhibitors were developed. However, we think that not all has been found, and importantly, novel PREP compounds are needed to take our research further - to clinical trials and drug on markets.