Institute of Biotechnology
(Visiting address: Viikinkaari 9)
00014 University of Helsinki
Tel +358 9 191 59358
Fax +358 9 1915 9366
University of Helsinki Business
Identity Code: FI-03134717
More funding for Mart Saarma's CDNF research from The Michael J. Fox Foundation for Parkinson's Research
Academy Professor Mart Saarma gets almost $ 180,000 from The Michael J. Fox Foundation for Parkinson's Research for his additional CDNF research for one year. MJFF has also funded Saarma's CDNF work with over a million US dollars in 2010-2012.
CDNF is a neurotrophic factor found by professor Mart Saarma group in 2003. CDNF has a unique mode of action, but its receptors and signaling pathways remain elusive. CDNF has neuroprotective effects that might be used in curing Parkinson's disease. Two neurotrophic factors GDNF and it homologue neurturin are in clinical trials but their clinical benefits have so far been very modest.
"One reason for this is that we don't know all that much about the optimal routes for neurotrophic factor delivery. CDNF has so far been delivered only to the striatum. The information about its efficacy after delivery to the substantia nigra and comparison with the efficacy of simultaneous infusion to striatum is critically important" Mart Saarma describes.
Now the MJFF has promised additional funding for Dr. Saarma's CDNF research. Mart Saarma will compare CDNF efficacy in rat 6-OHDA model of PD after CDNF delivery to the striatum, substantia nigra, or with simultaneous delivery to both substantia nigra and striatum.
Mart Saarma is the principal investigator of the project. The co-investigators are Dr. Mikko Airavaara, team leader at the Institute of Biotechnology and Professor Raimo K. Tuominen from the Faculty of Pharmacy.
Text: Elina Raukko
Photo: Kert Mätlik
Laminopathies: key components in the disease mechanism identified
A collaborative study between American and Finnish scientists shows that abnormal structure of the nuclear lamina, caused by laminopathy mutations, leads to changes in gene expression by disturbing the function of a specific transcription regulating protein.
Laminopathies are hereditary diseases that affect mainly the muscle tissue. These diseases include for example Emery-Dreifuss Muscular dystrophy, dilated cardiomyopathy, limb-girdle muscular dystrophy and Hutchison-Gilford progeria syndrome.
The underlying defect in these diseases is mutation in the genes encoding lamins or lamin-associated proteins. For example, many mutations in the lamin gene LMNA have been associated with different diseases.
Lamins are crucial components of the nuclear lamina that underlies the inner side of nuclear envelope, and provides mechanical stability to the nucleus. Lamina also participates in many different nuclear processes.
Two theories exist, why mutations in the lamina components cause disease. According to the first theory, mutations cause changes in the nuclear structure, which can lead to cell death in tissues that undergo harsh mechanical strain, such as the muscle. The second theory postulates that disturbed lamina causes changes in the gene expression patterns that are then deleterious for the cell.
A collaborative study between American and Finnish scientists bridge these two theories in a paper that was published Online Publication (AOP) of Nature
The study shows that abnormal structure of the nuclear lamina, caused by laminopathy mutations, lead to changes in gene expression by disturbing the function of a specific transcription regulating protein.
The researchers found out that in laminopathy cells, the regulation of SRF (serum response factor), which controls the expression of many important genes, is disturbed. The molecular basis for this is that LMNA mutations that cause laminopathy alter the cellular localization of emerin, which is an important constituent of the nuclear envelope. Emerin regulates actin in the cell nucleus, and actin in turn is a critical regulator of SRF activator MKL1. Therefore, mis-localized emerin in laminopathies results in reduced activation of SRF by MKL1, and reduced expression of SRF target genes. Because many SRF target genes are critical for muscle function, this finding explains, why laminopathies affect mainly this tissue type. It also gives a mechanistic link between altered nuclear envelope structure and gene expression.
This study will give a glimmer of hope to the patients suffering from laminopathies, by identifying key components that underlie the disease mechanism. Restoring MKL1 activity in laminopathies might be a productive intervention mechanism for these devastating diseases.
This study was done in collaboration between scientists from Cornell and Helsinki Universities, In Finland, the corresponding author is Maria Vartiainen from the Institute of Biotechnology, who is studying how the regulation of nuclear actin affects gene expression. In Finland, the study was funded by the Academy of Finland and Sigrid Juselius foundation.
In normal cells (upper panel), MKL1 (green) accumulates into the nucleus (red, blue) upon growth factor stimulation to activate SRF-mediated transcription. However, in cells with LMNA-mutations (lower panel), this accumulation is disturbed.
Text: Maria Vartiainen
Photo: Kaisa Rajakylä
3D simulation shows how form of complex organs evolves by natural selection
Researchers at the Institute of Biotechnology of the University of Helsinki have developed the first three-dimensional simulation of the evolution of morphology by integrating the mechanisms of genetic regulation that take place during embryo development. The study, published in Nature , highlights the real complexity of the genetic interactions that lead to adult organisms' phenotypes (physical forms), helps to explain how natural selection influences body form and leads towards much more realistic virtual experiments on evolution.
"Right now we have a lot of information on what changes in what genes cause what changes in form. But all this is merely descriptive. The issue is to understand the biological logic that determines which changes in form come from which changes in genes and how this can change the body", explains Isaac Salazar, a researcher at the University of Helsinki and lead author of the article. In nature this is determined by embryo development, during the life of each organism, and by evolution through natural selection, for each population and species.
But in the field of evolution of organisms it is practically impossible to set up experiments, given the long timescale these phenomena operate on. This means that there are still open debates, with hypotheses that are hard to prove experimentally. This difficulty is compensated for by the use of theoretical models to integrate in detail the existing experimental data, thus creating a virtual simulation of evolution.
The researchers used a theoretical model based on experiments on embryo development, on a previous study, also published in Nature (Salazar-Ciudad and Jernvall, 2010), and on three different mathematical models of virtual evolution by natural selection of form. Evolution takes place virtually on the computer in populations of individuals in which each individual can mutate its genes, just as this works in nature. Through the development model, these produce new morphologies and natural selection decides which ones pass on to the next generation. By repeating the process in each generation, we can see evolution in action on the computer.
This simulation enables a comparison of the different hypotheses in the field of evolution regarding which aspects of morphology evolve most easily. The first vision is that all metric aspects of form contribute to adaptation and that, consequently, all are fine-tuned by evolution over time. The second vision is that some aspects of form have greater adaptive value and that the remainder evolve collaterally from changes in these. The third is that no aspect of form is intrinsically more important, but what is important adaptively is a complex measurement of the form's roughness.
"What we have found is that the first hypothesis is not possible and that the second is possible in some cases. Even if ecology favoured this type of selection (the first vision), embryo development and the relationship between genetic and morphological variation imposed by this is too complex for every aspect of morphology to have been fine-tuned. In one way, what we are seeing is that natural selection is constantly modelling body forms, but these are still a long way from perfection in many ways", points out Salazar.
The study was led by Isaac Salazar-Ciudad and involved a PhD researcher, Miquel Marín Riera, from the Autonomous University of Barcelona. Isaac Salazar-Ciudad is part of the Helsinki "evo-devo" community (embryonic evolution and development) at the Institute of Biotechnology.
Real-time graph of virtual evolution process. The horizontal axis corresponds to evolution time and the vertical axis to the population's degree of evolutionary adaptation. In this case the form of the tooth adapts by increasing the number of tips, moving from a simple tooth to a more complex one.
Salazar-Ciudad I , Marín-Riera M. Adaptative dynamics under development-based genotype-Phenotype maps. Nature . 2013 May 1. doi: 10.1038/nature12142. [Epub ahead of print]
Text and photo: Isaac Salazar
A look at the latest publications
Matsuda S , Blanco J , Shimmi O . A Feed-Forward Loop Coupling Extracellular BMP Transport and Morphogenesis in Drosophila Wing. PLoS Genet . 2013; 9(3) :e1003403. (PubMed)
Miyashima S , Sebastian J, Lee JY, Helariutta Y . Stem cell function during plant vascular development. EMBO J . 2013; 32(2): 178-93. (PubMed)
Principal Investigator´s own web pages
- Annila lab
- Auvinen lab / DNAGEN
- Bamford lab
- Butcher lab
- Frilander lab
- Goldman lab
- Helariutta lab
- Hietakangas lab
- Holm lab
- Iwai lab
- Jernvall lab
- Jokitalo lab / EM
- Jäntti lab
- Lappalainen lab
- Löytynoja lab
- Mäkelä lab
- Mähönen lab
- Ojala lab
- Permi lab / NMR
- Pirvola lab
- Saarma lab
- Schulman lab
- Shimmi lab
- Thesleff lab
- Varjosalo lab / Proteomics unit
- Vartiainen lab
- Wikström lab
Team Leader ´s own web pages
- Ahola Tero
- Airavaara Mikko
- Andressoo Jaan-Olle
- Kajander Tommi
- Kaynak Bogac
- Mikkola Marja
- Nyman Tuula
- Salazar-Ciudad Isaac
- Vallenius Tea
- CoE in Metapopulation Research
- CoE in Molecular and Interactive Neuroscience Research
Academy of Finland Centres of Excellence operating in the Institute