Infrared analysis of neuronal proteins provides information about molecular changes in patients with ALS. This will help verify their diagnosis.
A research team from the Center for Protein Diagnostics (Prodi) at the Ruhr University Bochum (RUB) has developed a diagnostic tool for the rare neurological disease amyotrophic lateral sclerosis (ALS) in collaboration with scientists from the Technical University of Dresden, the University Hospital Essen and the University Hospital Göttingen. The study used the patented immune-infrared sensor to analyze changes in the folds of proteins in the cerebrospinal fluid (CSF) of ALS patients after specific binding. This novel method was the first to detect conformational changes in the protein TDP-43 in the patient’s CSF. The project team, led by Professor Klaus Gerwert and Professor Lars Tönges, published its research results from December 3, 2020 in the international journal “Annals of Clinical and Translational Neurology”.
Altered protein structures in ALS
ALS is a deadly neurodegenerative disease that leads to rapid loss of motor skills and usually leads to a serious disease with early death within a few years. Up until now, early and accurate diagnosis of the disease has been difficult. Stephen Hawking was one of the most famous patients. In the summer of 2014, the disease gained media attention through a large-scale fundraising campaign known as the Ice Bucket Challenge.
So far, one of the most important challenges in ALS diagnostics has been to rule out other mimicking diseases and to reliably verify an accurate diagnosis. The TDP-43 protein in particular plays a central role in ALS. It forms small inclusions in nerve cells. TDP-43 inclusions seem to have a decisive pathomechanistic importance and are the neuropathological markers in sporadic and many genetic ALS cases. They have been detected in numerous brain autopsies of ALS patients. In this study, the Bochum researchers and their colleagues showed that pathologically misfolded forms of the protein also occur in solution in the nerve fluid and can be specifically analyzed there.
Dr. Rene Günther, one of the main authors of the study and head of the research group and specialist outpatient department for motor neuron diseases at the Institute of Neurology at the Carl Gustav Carus University Clinic of the Technical University of Dresden, explains: “Biomarker research plays a crucial role in improving early detection and ensuring the diagnosis of Amyotrophic lateral sclerosis. In addition, biomarkers are a foundation for successful drug testing and therapy development in this dramatically progressive and difficult-to-treat disease. So far, only disease-specific biomarkers are available. In our pilot study, we used this innovative method to successfully identify conformational changes of TDP-43 proteins in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis for the first time. “
Pilot study shows potential
Lars Tönges and Klaus Gerwert’s team succeeded in diagnosing the disease based on the changed structure of the TDP-43 protein. The researchers showed that the proteins fold from mostly disordered and helical structures into so-called ß-sheets. These forms promote damage arrangements and deposits of the protein in nerve cells. In the analysis, 36 ALS patients were distinguished from 30 Parkinson’s patients using the TDP-43 signal with a sensitivity of 89 percent and a specificity of 77 percent. In addition, a control group with neurologically normal patients was differentiated with a sensitivity of 89 percent and a specificity of 83 percent. By analyzing TDP-43, the researchers were able to rule out other diseases that impair motor function, such as Parkinson’s disease. These results will be verified and validated in a larger study.
Optimization of the Alzheimer’s sensor
Klaus Gerwert’s immune infrared sensor has already been used in previous studies to detect pathologically altered proteins in the blood of Alzheimer’s patients before symptoms occur. In this case, the technology has been optimized and refined for use in the cerebrospinal fluid of patients with ALS. This shows that the method’s potential for other neurological diseases should also be explored. In close cooperation with Professor Ralf Gold, Director of the Department of Neurology at the St. Josef Hospital in Bochum and Research Director of the Prodi Department for Experimental Medicine, further projects are currently being carried out in order to gain a better understanding of the neurological disease processes.
Léon Beyer, one of the lead authors of the study and a PhD student at Prodi’s biospectroscopy department, says: “This achievement can provide new insights into the mechanisms of the disease. Compared to other methods that reflect the concentrations of certain proteins, our infrared sensor technology provides insights into molecular events and therefore may be a critical tool for the diagnosis and development of clinical therapies in the future. First and foremost, however, it will contribute significantly to a more precise understanding of diseases. “
The future will show value for clinical applications
In the future, the results of validation studies should provide information on whether the pathologically modified TDP-43 proteins can be used in clinical applications in order to enable earlier and more precise diagnoses and to gain new molecular knowledge.
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The study was carried out at the Center for Protein Diagnostics (funding code: 111.08.03.05-133974) and at the Pure Consortium (funding code: 233-1.08.03.03.-031-68079), which were funded by the Ministry of Culture and Science in North Rhine-Westphalia. In addition, the clinical studies were commissioned and financed by the Hermann and Lilly Schilling Foundation for Medical Research in the Stifterverband.
Léon Beyer *, René Günther *, Lars Tönges #, Klaus Gerwert # among others: TDP-43 as a structure-based biomarker in amyotrophic lateral sclerosis, in: Annals of Clinical and Translational Neurology, 2020, DOI: 10.1002 / acn3.51256
* joined lead authors, # joined older authors
Prof. Prof. DR. Lars Tönges
Department of Neurology
St. Josef Hospital
Phone: +49 234 509 2420 42
Prof. Prof. DR. Klaus Gerwert
Center for Protein Diagnostics
Phone: +49 234 32 18035