New biosensor detects cell-to-cell transmission of the Parkinson-associated protein alpha-Synuclein

Human alpha-synuclein (hαSyn) is a physiological protein that is primarily found in nerve cells, and is involved in the development of various neuro-degenerative diseases, such as Parkinson's disease, Lewy-Body dementia and multisystem atrophy.

In the course of these devastating diseases, hαSyn can form larger insoluble aggregates or middle size oligomers, which lead to the death of the affected nerve cells in the brain. Recent studies also show that these toxic aggregates are transmitted from one nerve cell to the next nerve cell by a mechanism similar to that of prion diseases.

However, there is a controversial debate in basic research about how this process takes place exactly.

Scientists at the Göttingen Center for Biostructural Imaging of Neurodegeneration (BIN) of the University Medical Center Göttingen have now succeeded in developing a biosensor that can be used to visualize the transmission of the hαSyn protein between neurons.

In the recently published study, the teams of Dr. Felipe Opazo (BIN) and Prof. Dr. Silvio O. Rizzoli, Institute of Neuro- and Sensory Physiology (UMG), describe the development of the biosensor “Fluorescent Reporter for Human αSyn”, in short FluoReSyn.

The results presented here prove that the new FluoReSyn biosensor can become a valuable tool for investigating the transmission of human alpha-synuclein, and has great potential for clinical research and diagnostics.

For the first time, the new biosensor allows the reliable observation in cultured nerve cells and in animal models of how the hαSyn protein transmits its message from cell to cell.

The new biosensor therefore is a suitable tool to decipher the molecular mechanisms of hαSyn-associated neurodegenerative diseases. The study was funded by the Göttingen Cluster of Excellence Multiscale Bioimaging: from molecular machines to networks of excitable cells (MBExC) and published in the renowned journal “Nature Communications”.

Original publication:Gerdes C, Waal N, Offner T, Fornasiero EF, Wender N, Verbarg H, Manzini I, Trenkwalder C, Mollenhauer B, Strohaeker T, Zweckstetter M, Becker S, Rizzoli SO, Basmanav FB, Opazo F (2020) A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol. NAT COMMUN, 11: 2729 (2020). DOI: 10.1038/s41467-020-16575-0

Prerequisite for the development of preventive and therapeutic strategies for synuclein-associated, neurodegenerative diseases is a fundamental understanding of the molecular mechanisms that lead to the development and spread of these dissases. The development of the FluoReSyn biomarker represents a major step forward in the study of these mechanisms.

“The presented results prove that FluoReSyn is a very useful tool to study the transmission mechanism of hαSyn. After appropriate optimization, our biosensor may even be able to serve as a diagnostic marker for αSyn-associated neuro-degenerative diseases”, says Dr. Felipe Opazo, senior author of the publication.

New Biosensor FluoReSyn

The methods used to date for detection of hαSyn transmission are based either on genetic manipulation of the protein or pre-labelling using fluorescent markers. These methods are criticised because they may alter the physiological structure of hαSyn, and can thus lead to an impairment of the natural function and localisation of this protein.

The team of Dr. Opazo used anibodies derived from alpacas, also known as “nanobodies” due to their miniatured size. These nanobodies can be engeniered to carry a fluorescent molecule and they have the unique ability to be used as reporters in living cells.

Whith this technology, the present study characterized the Fluo-ReSyn biosensor, which is able to reveal the entrance of external hαSyn proteins (transmission), and enables to detect hαSyn in a dose-dependent manner. Using cells, that stably express FluoReSyn, the scientists interestingly succeeded in detecting the entrance of a transmittable form of hαSyn from cerebrospinal fluid of Parkinson patients.

The Göttingen Cluster of Excellence Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells (MBExC) is funded since January 2019 in the framework of the Excellence Strategy of the German Federal and State Gov-ernments. Applying a unique and multiscale approach, MBExC investigates the disease-relevant functional units of electrically active cells of heart and brain, from the molecular to the organ level.

The MBExC unites numerous partners from the university and extra-university institutions in Göttingen. The overall goal: to under-stand the relationship between heart and brain diseases, to link basic and clinical research, and thus to develop new therapeutic and diagnostic approaches with social implications.

FURTHER INFORMATIONEN
Lab of Dr. Felipe Opazo: https://opazolab.de
Lab of Prof. Rizzoli: http://www.rizzoli-lab.de
About BIN: https://www.cfbin.uni-goettingen.de
About MBExC: https://mbexc.de

University Medical Center Göttingen
Center for Biostructural Imaging of Neurodegeneration (BIN)
Dr. Felipe Opazo
Von Siebold-Str. 3a, D-37075 Göttingen
Phone 0551 39-61156; Email: fopazo@gwdg.de

University Medical Center Göttingen
Institute for Neuro- and Sensory Physiology
Prof. Dr. Silvio O. Rizzoli
Humboldtallee 23, D-37073 Göttingen
Phone 0551 39-5911; Email: srizzol@gwdg.de

University Medical Center Göttingen
Center for Biostructural Imaging of Neurodegeneration (BIN)
Dr. Felipe Opazo
Von Siebold-Str. 3a, D-37075 Göttingen
Phone 0551 39-61156; Email: fopazo@gwdg.de

University Medical Center Göttingen
Institute for Neuro- and Sensory Physiology
Prof. Dr. Silvio O. Rizzoli
Humboldtallee 23, D-37073 Göttingen
Phone 0551 39-5911; Email: srizzol@gwdg.de

Original publication:Gerdes C, Waal N, Offner T, Fornasiero EF, Wender N, Verbarg H, Manzini I, Trenkwalder C, Mollenhauer B, Strohaeker T, Zweckstetter M, Becker S, Rizzoli SO, Basmanav FB, Opazo F (2020) A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol. NAT COMMUN, 11: 2729 (2020). DOI: 10.1038/s41467-020-16575-0