Biomarkers and target proteins identified in vulnerable neurons
FRANKFURT Parkinson's Disease is the second most common neurodegenerative disorder. In Germany alone, almost half a million people are affected. The focus of the disease is the progressive degeneration of dopamine-producing nerve cells in a certain region of the midbrain, the substantia nigra. Misfolded proteins are the cause. Until recently, it was unclear why damage is confined to specific nerve cells. A team or researchers led by Frankfurt neurophysiologists has now defined how this selective disease process begins using a genetic mouse model of Parkinson´s disease.
The progressive death of a certain type of nerve cells – dopaminergic neurons - in the substantia nigra causes dopamine deficiency, which is the major cause for the motor deficits in Parkinson patients. Although it is possible to therapeutically compensate the dopamine deficiency for a certain period of time, by e.g. administration of L-dopa or dopamine agonists, these therapies do not stop the progressive death of neurons.
In the last two decades, researchers have identified gene mutations and toxic protein aggregates to cause neurodegeneration, with the protein a-synuclein having an essential role. Until recently, it was unclear why only specific types of nerve cells, such as dopaninergic neurons in the substantia nigra, are affected by this process, while others, also expressing the mutant a-syncuclein such as dopaminergic neurons in the immediate vicinity, survive the disease process with little damage.
The research group led by Dr. Mahalakshmi Subramaniam and Prof. Jochen Roeper at the Institute for Neurophysiology at the Goethe University, in collaboration with researchers from Frankfurt's Experimental Neurology Group and from Freiburg University, demonstrated for the first time how sensitive dopaminergic substantia nigra neurons functionally respond to toxic proteins in a genetic mouse model. A mutated a-synculein gene (A53T), which causes Parkinson's Disease in humans, is expressed in the mouse model.
In the current issue of the Journal of Neuroscience, the researchers report that the sensitive dopaminergic substantia nigra neurons respond to the accumulation of toxic protein by significantly increasing the electric activity in the affected midbrain regions. In contrast, the less sensitive, neighboring dopaminergic neurons were not affected in their activity. "This process begins as early as one year before the first deficits appear in the dopamine system, and as such it presents an early functional biomarker that may have future potential for preclinical detection of impending Parkinson's Disease in humans," explains Prof. Jochen Roeper. "The potential for early preclinical detection of subjects at risk is essential for the development of neuroprotective therapies."
The Frankfurt group, also identified a regulatory protein, an ion channel, which is causes the increase in electric activity and the associated stress in nerve cells in response to oxidative damage. This channel provides a direct new target protein for the neuroprotection of dopaminergic neurons. In brain slices, the dysfunction of this ion channel acting as an "electric brake" for dopamine neurons was reversible just by adding redox buffers. If therapeutic drugs could reduce the channel´s redox sensitivity in future mouse models, the death of dopaminergic neurons in the substantia nigra might be prevented. Currently, the researchers are studying whether similar processes occur with other Parkinson genes and in aging itself. "The long-term objective is to investigate the extent to which these results from mice might be transferred to humans," says Roeper.
Publikation: Mahalakshmi Subramaniam et al.: Mutant a-Synuclein Enhances Firing Frequencies in Dopamine Substantia Nigra Neurons by Oxidative Impairment of A-Type Potassium Channels, The Journal of Neuroscience, October 8, 2014 • 34(41):13586 –13599. doi:10.1523/JNEUROSCI.5069-13.2014.
Information: Prof. Dr. med. Jochen Roeper, Institute of Neurophysiology Goethe University Frankfurt, Phone +49(0)69 6301–84091, firstname.lastname@example.org.
A research group lead by scientists at the Goethe University Frankfurt discover details on how clouds form
FRANKFURT. New insights into cloud formation were obtained by scientists from the Goethe University of Frankfurt in an international collaboration. They found out that amines could play an important role in aerosol formation. They act as a kind of “superglue”. Aerosol particles influence the climate through their role in cloud formation because clouds can only form if so-called cloud condensation nuclei (CCN) are available.
It has been known for several years that sulfuric acid contributes to the formation of tiny aerosol particles, which play an important role in the formation of clouds. The new study by Kürten et al. shows that dimethylamine can tremendously enhance new particle formation. The formation of neutral (i.e. uncharged) nucleating clusters of sulfuric acid and dimethylamine was observed for the first time.
Previously, it was only possible to detect neutral clusters containing up to two sulfuric acid molecules. However, in the present study molecular clusters containing up to 14 sulfuric acid and 16 dimethylamine molecules were detected and their growth by attachment of individual molecules was observed in real-time starting from just one molecule. Moreover, these measurements were made at concentrations of sulfuric acid and dimethylamine corresponding to atmospheric levels (less than 1 molecule of sulfuric acid per 1 x 1013 molecules of air).
The capability of sulfuric acid molecules together with water and ammonia to form clusters and particles has been recognized for several years. However, clusters which form in this manner can vaporize under the conditions which exist in the atmosphere. In contrast, the system of sulfuric acid and dimethylamine forms particles much more efficiently because even the smallest clusters are essentially stable against evaporation. In this respect dimethylamine can act as “superglue” because when interacting with sulfuric acid every collision between a cluster and a sulfuric acid molecule bonds them together irreversibly. Sulphuric acid as well as amines in the present day atmosphere have mainly anthropogenic sources. Sulphuric acid is derived mainly from the oxidation of sulphur dioxide while amines stem, for example, from animal husbandry. The method used to measure the neutral clusters utilizes a combination of a mass spectrometer and a chemical ionization source, which was developed by the University of Frankfurt and the University of Helsinki. The measurements were made by an international collaboration at the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber at CERN (European Organization for Nuclear Research).
The results allow for very detailed insight into a chemical system which could be relevant for atmospheric particle formation. Aerosol particles influence the Earth’s climate through cloud formation: Clouds can only form if so-called cloud condensation nuclei (CCN) are present, which act as seeds for condensing water molecules. Globally about half the CCN originate from a secondary process which involves the formation of small clusters and particles in the very first step followed by growth to sizes of at least 50 nanometers. The observed process of particle formation from sulfuric acid and dimethylamine could also be relevant for the formation of CCN. A high concentration of CCN generally leads to the formation of clouds with a high concentration of small droplets; whereas fewer CCN lead to clouds with few large droplets. Earth’s radiation budget, climate as well as precipitation patterns can be influenced in this manner. The deployed method will also open a new window for future measurements of particle formation in other chemical systems.
Kürten, A., Jokinen, T., Simon, M., Sipilä, M., Sarnela, N., Junninen, H., Adamov, A., Almeida, J., Amorim, A., Bianchi, F., Breitenlechner, M., Dommen, J., Donahue, N. M., Duplissy, J., Ehrhart, S., Flagan, R. C., Franchin, A., Hakala, J., Hansel, A., Heinritzi, M., Hutterli, M., Kangasluoma, J., Kirkby, J., Laaksonen, A., Lehtipalo, K., Leiminger, M., Makhmutov, V., Mathot, S., Onnela, A., Petäjä, T., Praplan, A. P., Riccobono, F., Rissanen, M. P., Rondo, L., Schobesberger, S., Seinfeld, J. H., Steiner, G., Tomé, A., Tröstl, J., Winkler, P. M., Williamson, C., Wimmer, D., Ye, P., Baltensperger, U., Carslaw, K. S., Kulmala, M., Worsnop, D. R., and Curtius, J.: Neutral molecular cluster formation of sulfuric acid-dimethylamine observed in real-time under atmospheric conditions, Proc. Natl. Acad. Sci. USA, doi/10.1073/pnas.1404853111, 2014.
Contact: Dr. Andreas Kürten, Institute for Atmospheric and Environmental Sciences, Goethe University Frankfurt am Main, Telefon 0049 (69) 798-40256, E-Mail: email@example.com