New target for Parkinson's disease therapy? Blockade of specific calcium channels can protect nerve cells

Progressive degeneration of dopamine-producing nerve cells in the brain leads to dopamine deficiency and ultimately to Parkinson’s disease. Scientists from Ulm University in Germany, together with partners from Cologne and Oxford, have now investigated this process in more detail. The researchers were able to show that the inactivation of a specific calcium channel (Cav2.3 R-type) can prevent neurodegeneration. The results were published recently in the journal Nature Communications.

Parkinson's disease is the second most common neurodegenerative disease. Worldwide, about six million patients are affected, and the number continues to rise. The progressive loss of dopamine-releasing nerve cells in the so-called black matter causes the typical motor symptoms in Parkinson’s patients, such as resting tremor and muscle stiffness.

Antibody staining of mouse dopamine-producing nerve cells (green). Cav2.3 channels are stained red. Scale bar: 10 µm (figure: © Benkert et al., Nature Communications)

In their new study, researchers at Ulm University led by Professor Birgit Liss, Director of the Institute of Applied Physiology, have examined the degeneration of dopamine-producing neurones and their high sensitivity to Parkinson's stressors. The scientists were able to identify a special voltage-gated ion channel, namely an R-type calcium channel, also known as Cav2.3. 'Together with our partners, we've discovered that this channel, which had not been linked to Parkinson's disease before, is important for the physiological function of the vulnerable neurons. The channel lets calcium into the cells. Ongoing closure of the channel, however, protects the nerve cells from degeneration in Parkinson's models,' said Liss. 'Calcium is important for a variety of cell functions, but too much of it can lead to cell death.̕

Julia Benkert, first author of the study (photo: Dr. Johanna Duda)

'Our research on Parkinson's patients indicates that in humans, Cav2.3 channels appear to be involved in signalling cascades similar to those in mice,' explains first author Julia Benkert, who is a PhD-student at the Institute of Applied Physiology. 'Cav2.3 channel opening is controlled by the activity of the vulnerable neurons, and mediates transiently increased calcium levels in the cells.'

A recent phase-III clinical trial with a drug called isradipine has failed. Isradipine blocks a different type of calcium channel. Although epidemiological evidence links the use of such blockers to a reduced risk for Parkinson's disease, isradipine did not affect disease-progression in this study. 'The reasons for this can be manifold - our findings might provide one explanation,' the researchers say.

Prof. Dr. Birgit Liss, Director of the Institute of Applied Physiology (photo: Sascha Baumann I all4foto)

Currently, there is no therapy available that can cure Parkinson’s or at least slow its progression. With their work, the scientists have defined a new possible approach for such a therapy: inactivation of Cav2.3 channels - alone or in combination with other channels.

The study was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft), the Austrian Science Fund and other funding agencies.


Further information: Prof. Dr. Birgit Liss, Institute of Applied Physiology, birgit.liss@uni-ulm.de, phone: +49 731 50036214


Image captions:
Figure 1 (© Benkert et al., Nature Communications): Antibody staining of mouse dopamine-producing nerve cells (green). Cav2.3 channels are stained red. Scale bar: 10 µm
Birgit Liss (photo: Sascha Baumann I all4foto): Prof. Dr. Birgit Liss, Director of the Institute of Applied Physiology
Julia Benkert (photo: Dr. Johanna Duda): Julia Benkert, first author of the study


Publication reference:
Julia Benkert, Simon Hess, Shoumik Roy, Dayne Beccano-Kelly, Nicole Wiederspohn, Johanna Duda, Carsten Simons, Komal Patil, Aisylu Gaifullina, Nadja Mannal, Elena Dragicevic, Desireé Spaich, Sonja Müller, Julia Nemeth, Helene Hollmann, Nora Deuter, Yassine Mousba, Christian Kubisch, Christina Poetschke, Joerg Striessnig, Olaf Pongs, Toni Schneider, Richard Wade-Martins, Sadip Patel, Rosanna Parlato, Tobias Frank, Peter Kloppenburg & Birgit Liss: Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease. Nature Communication 08 November 2019 https://doi.org/10.1038/s41467-019-12834-x

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