“My research aims to understand critical mechanisms in protein homeostasis that underlie health and disease in the brain.”
Professor, Pharmacology and Drug Development
Division of Pharmacology and pharmacotherapy
Vice dean for research, Faculty of Pharmacy, University of Helsinki
Group leader, Neuroscience Center, HiLIFE, University of Helsinki
What are your research topics?
Our research is focused on two significant diseases with substantial unmet medical needs, Parkinson’s disease and stroke. Parkinson’s disease is the second most common neurodegenerative disease, it is progressive, and there are no disease-modifying drug treatments. Stroke is the second most common cause of death globally and the leading cause of disability, and despite some success in acute treatments, recovery is slow, and there are no drugs that would hasten the recovery. Our focus is from the preclinical, experimental neurology, and mechanisms point of view. The ultimate long-term goal is to develop disease-modifying therapies- based on fundamental science and new mechanisms- that are currently lacking for neurodegeneration.
Based on your research, what is (are) the most central, most urgent, or most exciting unresolved question(s) in your research field?
We have been working for a long time with proteins located in the endoplasmic reticulum lumen, and these proteins have pleiotropic effects, and they have shown efficacy in various disease models of brain and peripheral organ diseases. We start to understand how these proteins act in what their mechanisms are in the lumen of the endoplasmic reticulum, but we still know very little about how they mediated their protective effects when applied extracellularly. Interestingly protein folding capacity decreases in aging in almost all species studied, underlying the importance of these studies.
We are also curious about the heterogeneity of the endoplasmic reticulum in the regulation of protein homeostasis in different brain cells, and this is a topic that we do not know anything about. We have long-known heterogeneity between neurons and know several different neuronal phenotypes. We are now starting to understand heterogeneity between different glial cells, and in fact, we think that we are now at the frontier where we begin to understand these different phenotypes between microglia and among other glial cells such as astrocytes, oligodendrocytes, or oligodendrocyte precursors. After that, we might have the capacity and technologies that we could start to understand heterogeneity between endoplasmic reticulum between different brain cells and maybe even between different phenotypes of each cell type. There will be a lot of new drug targets to study, but this will take decades.
In line, we are also interested in protein aggregation in the cytosol of brain cells. We have developed a novel Lewy body model in primary dopamine neurons and can carry out small molecule screening with high-content image analysis to decrease the number of dopamine neurons with Lewy bodies. Importantly, we have positive control in our studies. In the future, we aim to understand what the critical quality control failures in neurons are that lead to Lewy body-like inclusions, and we aim to identify novel mechanisms that maintain dopamine neuron phenotype.
Also, inflammation plays an essential role in Parkinson’s disease and stroke, and we aim to understand myeloid cell and neuron interactions. In stroke, what happens is that acutely there is a massive number of dead cells that are surrounded by healthier tissue. Based on our work and others, we know that the clearance of dead cells is slow. In the Brain Repair group, we want to test the idea that if we facilitate inflammation and promote the removal of dead cells, does it lead to faster recovery from stroke and understand how inflammation contributes to the disease? Our model systems give an excellent opportunity to test it.