Pharmacology of degenerative brain diseases


Raimo Tuominen's group

Principal investigator: Professor Raimo K. Tuominen.

Protein kinase C (PKC) as drug target

There are ten isoforms of PKC in the human genome, and all of them regulate cell proliferation, survival, differentiation, migration and apoptosis – processes that are disturbed in cancer and in neurodegenerative disorders such as in Alzheimer’s disease (AD). The C1 domain of PKC is a binding site for the physiological activator DAG and as a drug target it provides a possibility to develop both PKC inhibitors and activators. Additionally, many of the other six families of C1 domain-containing proteins (such as chimaerins, protein kinase D and MRCK) also regulate cell proliferation, migration and apoptosis. According to current knowledge, targeting the C1 domain provides a possibility to influence several cancer-related signaling pathways simultaneously. We have developed small molecule compounds that penetrate cell membranes and are able to modify PKC-activity as they bind to the C1-regulatory domain of the enzyme. In addition, the compounds bind to the C1 domains of chimaerins, PKD and MRCK with comparable affinities as to PKC. Two of our lead compounds possess encouraging activities in cell-based models of cancer and AD. Our aim is to study in detail their effects in cell-based models and in animal models of these diseases, and improve their properties as drug candidates.

CDNF and MANF in experimental model of PD

Prevalence of Parkinson’s disease (PD) is 1 % among people aged over 60 years. Neuropathology of PD is mainly characterized by degeneration of midbrain dopamine neurons. Our research aims at disease modifying therapy of PD by using neurotrophic factors (NTF) that would halt neurodegeneration and even rescue dying neurons. NTFs such as glial cell-line derived neurotrophic factor (GDNF) and its homologous protein NRTN have been studied in parkinsonian patients with promising results in a subset of patients. Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte cell-line derived neurotrophic factor (MANF) form an evolutionarily conserved family of NTFs. They show neuroprotective effects in animal models of PD that are comparable or even better that those of GDNF. In relation to the effects of the NTFs we will study mechanisms by which neural progenitor cells could be induced and differentiated to dopamine neurons. The induction of progenitor cells follows the idea of using stem in therapy of PD.


Pekka Männistö's group

Principal investigator: Professor Pekka T. Männistö

Prof. Pekka T. Männistö has retired from his professorship position 1st of January 2013 and is finalising his publications.


Petteri Piepponen's group

Principal investigator: Docent T. Petteri Piepponen

Mechanisms of alcohol addiction

(co-PI prof. Atso Raasmaja)

Alcohol is a leading cause of death among men and women of working age in Finland, and the costs of alcohol abuse for the society are enormous. The burden of alcohol-related health and social consequences could be managed with treatments and other interventions. However, development of effective pharmacotherapies relies on our understanding of the mechanisms of alcohol addiction. We aim to clarify the role of brain opioidergic systems in alcohol addiction and craving as well as relapse after withdrawal using the animal model of alcohol-preferring rats. By using viral vectors, we will increase and decrease the expression of mu and kappa-opioid receptors locally in the brain and investigate their role in alcohol self-administration and relapse. In addition, we test novel pharmacological treatments for alcohol addiction and craving.  The project is a co-operation with Finnish National Institute for Health and Welfare (prof. Kalervo Kiianmaa).

Neuronal mechanisms of gambling

(co-PI prof. Atso Raasmaja)

Pathological gambling, a disorder affecting approximately 1.6 % of the adult population, is characterized by excessive time consumed to gambling or thinking about gambling, needing to gamble with increasing amounts of money, chasing one’s losses, unsuccessful efforts to stop gambling and financial/social problems due to gambling. Thus, gambling shares many common features with substance addictions. We have developed an animal model of gambling by which we aim to characterize the role most important neurotransmitter systems (opioidergic, dopaminergic, serotonergic) and brain areas involved in gambling behavior. The project is a co-operation with the Finnish National Institute for Health and Welfare (prof. Kalervo Kiianmaa).

Role of GDNF family neurotrophic factors in the development and maintenance of midbrain dopaminergic systems

Glial cell line-derived neurotrophic factor (GDNF) has been identified as a potent neurotrophic factor for midbrain dopamine neurons. With genetically modified animal models we investigate the role of GDNF on midbrain dopaminergic systems from the early development until high age by using a wide variety of neurochemical and behavioural models. The project is a co-operation with the Institute of Biotechnology, University of Helsinki (prof. Mart Saarma, Dr. Jaan-Olle Andressoo).

Role of GDNF family neurotrophic factors in drug addiction and craving

Drug addiction can be regarded as a pathological form of neural plasticity reflected by long lasting or permanent changes in behaviour of both human beings and experimental animals. GDNF appears to have a role in the long-lasting/persistent effects of drugs of abuse. In this project we aim to characterize the role and mechanisms of action of neurotrophic factor GDNF in the plastic changes occurring during the course of repeated exposure to drugs of abuse. We combine genetic animal models with behavioural and neurochemical methods related to addictive behaviour. The project is a co-operation with the Institute of Biotechnology, University of Helsinki (prof. Mart Saarma, Dr. Jaan-Olle Andressoo).


Outi Salminen's group

Principal investigator: Docent Outi Salminen.

Distinct nicotinic acetylcholine receptors in dorsal and ventral striatum: Basis for novel therapies of Parkinson’s disease

The golden standard therapy for Parkinson’s disease is levodopa. However, levodopa treatment is plagued by adverse effects, especially dyskinesias that affect the whole body. Presently, there is no effective drug therapy against dyskinesias. In animal models, it has been shown that nicotinic drugs could be effective in treating this severe adverse effect. This study aims at clarifying the mechanisms of levodopa-induced dyskinesias and, further, how nicotine elicits its antidyskinetic effect. The aim of this project is to build the basis for development of improved drug therapy for currently poorly treated aspects of Parkinson’s disease.

Nicotine-opioid interactions – molecular mechanisms and brain neurochemistry in transgenic mice

Tobacco smoking is a leading cause of preventable morbidity globally. The main pharmacological substance causing tobacco addiction is nicotine, whose effects are mediated via neuronal nicotinic acetylcholine receptors (nAChRs). Activation of brain nAChRs leads to changes in the activity of neural circuits including the release of dopamine, glutamate, GABA and endogenous opiates in specific brain areas. Thus, nicotine may also modify responses of other drugs of abuse, like opioids, affecting these neural circuits. We have shown earlier in cell lines and animals models that nicotine and opioids have common biochemical mechanisms, which warrant further studies. In this project, we will study nicotine-opioid interaction in systematic way using various opioid agonists and antagonists as tools. In order to dissect the significance of the various subtypes of nAChRs in nicotine-opioid interactions we will use cell-lines expressing nAChR subtypes (α7)5 and (α4)2β2)3 and also SHSY5Y cell line expressing several nAChRs. Nicotine-opioid interactions will be evaluated in genetically modified nAChR knock-out and knock-in mice.


Arturo García-Horman's group

Principal investigator: Docent J. Arturo García-Horman.

Physiology of peptidases and their relevance in neurodegeneration

In this project the goal is to find the peptide homeostasis regulation in health and disease, and discover the role of specific peptidases and their regulators. Special attention is taken to prolyl oligopeptidase (PREP), α-2-macroglobulin, somatostatin, and derivatives from fibrinogen and collagen. This research is conducted with particular focus on neuroinflammatory diseases like multiple sclerosis and hepatic encephalopathy.

Development of platforms for screening peptides/peptidases for neurodegenerative diseases diagnosis

The goal is to design high throughput methods for the detection of several peptidases at the same time in order to build a peptidase fingerprint for neurodegenerative diseases. We and our collaborators have measured levels of different peptidases in tissue and plasma samples of neurodegenerative disease patients and animal models and hypothetical fingerprints have already been proposed.

Development of imaging non-invasive methods for detection of neuroinflammation

The goal is to develop new tracers, based on newly discovered events in peptidase expression during neuroinflammation, to be used as radio-ligands for single photon emission computed tomography (SPECT) or positron emission tomography (PET). This is based on our latest discovery that dramatic changes in prolyl oligopeptidase (PREP) activity and levels are primary events during glial activation.


Timo Myöhänen's group

Principal investigator: Docent Timo T. Myöhänen.

PREP in neurodegenerative diseases

α-synuclein is a brain protein that has specific functions in e.g. dopamine neurotransmission – this neuronal population is destroyed in Parkinson’s disease. In Parkinson’s disease, α-synuclein accumulates in neurons causing them to malfunction and ultimately die. One of the factors affecting α-synuclein accumulation is prolyl oligopeptidase (PREP), an enzyme that is widely distributed among species and organs but whose physiological function remains unclear. Notably, the effect of PREP on α-synuclein aggregation can be reversed by using specific PREP enzyme inhibitors. Our research is focused on understanding the mechanisms of how PREP increases the accumulation of α-synuclein, and whether PREP inhibitors are effective in preventing α-synuclein accumulation or even dissolving the surplus of α-synuclein from cells. Moreover, we study the role of PREP and its inhibition on neuron related movement regulation, and the possible role of PREP on other protein aggregation diseases.

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