Our research focuses mainly on  neurodegenerative diseases with protein accumulation. These diseases contain Parkinson’s and Alzheimer’s diseases as the most common and known ones but toxic protein accumulation is also seen in various other neurodegenerative diseases, such as Huntington’s diseases, multiple system athropy, frontotemporal dementia… Common factor for these diseases is abnormal accumulation of protein in neurons and neuronal death.

This results to clinical symptoms that are related to degenerated brain area – e.g. in Parkinson’s disease neurons in the areas of the brain that are involved in motor activity degenerate and lose their ability to function and this leads to clinical Parkinson’s symptoms, such as resting tremor, muscle rigidity and difficulties starting movement. Then again in the Alzheimer’s disease brain areas involved in memory and learning shrink, leading to problems in memory and cognitive functions.

Neurodegenerative diseases are becoming more common

Approximately 1% of all people over the age of 60 will develop Parkinson’s disease and 8% will have Alzheimer’s disease or other dementia. There are currently 10,000 Parkinson’s patients and 70,000 Alzheimer’s patients in Finland, and in the future, the number will further increase due to the aging of the population in First World countries.

There is no cure for neurodegenerative diseases

Dopaminergic cells in rat substantia nigra – these cells are degenerated in Parkinson’s disease

It is currently unknown what causes neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, and there is currently no curative or delaying treatment for theses diseases. Current drug therapies are based to relieve symptoms but unfortunately, they cannot modify or even delay the progress of the disease. Therefore, there is a need for novel drug therapies that are able to delay and, in the best scenario, stop the progress of the disease.

PREP enzyme inhibitors to stop the progress of neurodegeneration?

PREP protein in human Substantia nigra

Although the causes are unknown, several factors affecting the progress neurodegeneration have been found. One of the key players is abnormal and toxic accumulation of proteins. In Parkinson’s disease the accumulating protein is α-synuclein. α-synuclein is a brain protein that has specific functions in e.g. dopamine neurotransmission. In Parkinson’s disease, α-synuclein accumulates neurons causing them to malfunction and ultimately die. Several compounds can increase the misfolding and accumulation of α-synuclein, at least in various cellular and animal models. In Alzheimer’s disease, the best known accumulating protein is beta-amyloid but other, maybe even more toxic badly-behaving protein is Tau. Tau accumulations are also seen in several other diseases called Taupathies (e.g. frontotemporal dementia, Pick’s disease and CTE). Tau normally stabilizes cell skeleton but in Alzheimer’s disease, it gets released from its normal location and starts to accumulate inside the cells, causing several toxic features. PREP (EC 3.4.21.26), a serine protease, was recently found, in an in vitro study, to increase the misfolding of α-synuclein. Most importantly, PREP enzyme inhibitors were able to block this action, and our current studies also suggest that PREP inhibition not only blocks the aggregation process but also increases the clearance of α-synuclein accumulations from cells. This clearance action can be beneficial to decrease also other intracellular protein aggregates, like Tau.

Our research focuses on studying the role of prolyl oligopeptidase (PREP, POP) in neurodegeneration, and the possibilities of PREP inhibitors as drug therapy for Parkinson’s and Alzheimer’s disease. You can find more information about our studies in PREP research.