At present, the definite diagnosis of PD can be made only after death by examining the pathology in brain of deceased patients. Diagnosis assesses the presence of clumps within specific brain areas made up primarily of alpha-synuclein. In such pathological inclusions, the alpha-synuclein protein phosphorylated at position serine-129 (PSer129). This proposal aims at a biomarker for the early detection and monitoring disease progression by developing a method capable of detecting PSer129 in body fluids.
The amounts of PSer129 in body fluids are extremely low, and not detectable with current protein-based methods. We propose to develop a technique that takes advantage of the strong and reliable signal amplification by the DNA polymerase chain reaction (PCR), which has revolutionized basic research and forensics. The trick is to combine DNA (template) and antibodies (probe) in a method called immuno-PCR. The applicant’s contractors are pioneers in the field of immuno-PCR and molecular diagnosis. Once the method is established with synthetic material produced in the applicant’s laboratory, it will be taken to an extensive series of measurements on human samples. The co-PI (Prof. Gasser) is a world-class leading expert in PD genetics and biomarkers, and runs the largest PD biobank in Germany.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The symptoms of PD can be treated for some time with dopaminergic drugs, but it cannot be cured let alone prevented. Part of the problem is that by the time symptoms have progressed to the point at whic patients realize they suffer from PD, most of the affected brain cells have died. Thus it is pivotal to identify individuals at risk as early as possible to allow for more clinical intervention time. In addition, the benefit of new therapeutic approaches needs to be monitored by objective biomarkers.
Should we manage to develop for the first time a method sensitive and reproducible enough to detect PSer129 in human body fluids, we will be able to test if PSer129 diagnoses PD patients very early on. We shall also see if PSer129 increases with increasing disease duration/severity. As PSer129 appears to be causally related to PD pathogenesis, it might eventually be used to monitor future therapeutic approaches directly interfering with this process.