Development of alpha-synuclein as a potential molecular marker for Parkinson s disease

Parkinson?s disease (PD) is a common, incurable brain disease, with characteristic symptoms including tremors of the hands, muscle rigidity and slowness of movement. In PD, structures called ?Lewy bodies? are found inside nerve cells in affected regions of the brain. Lewy bodies contain abnormal fibres made out of a protein called alpha-synuclein and the formation of these alpha-synuclein deposits inside Lewy bodies is an important step in the development of PD. Interestingly, we have found that alpha-synuclein is also present in human blood. Furthermore, the levels of this protein appear to be altered in blood samples from patients with PD. We now propose to set up an extensive study to determine if alpha-synuclein in blood can be used as a diagnostic marker to help to discriminate PD from other movement disorders, or to follow the clinical progression of the disease. We will also run a clinical trial on a potential new drug for PD and as part of this trial we will monitor the effects of this drug on alpha-synuclein levels in blood. This will help us to determine if alpha-synuclein can be used as a marker in many future drug trials. Ultimately, it is hoped that a blood test can be developed to allow detection of PD during its early stages, when treatment is likely to be most effective. The development of alpha-synuclein as a biological marker would be expected to lead to major improvements in the treatment and quality of life of people with PD.

This proposal is focussed around the development of a protein called alpha-synuclein as a potential novel molecular marker for Parkinson?s disease (PD). This protein plays a key role in the histopathology and genetics of PD, and we have discovered that alpha-synuclein is present in human body fluids, including blood plasma. Recently, we have published preliminary evidence, involving relatively small scale studies, that the levels of this protein in cerebrospinal fluid and blood plasma are altered in patients with PD compared to controls, and that these levels can correlate with the clinical severity of disease. We now propose to carry out an extensive investigation into both normal and pathological forms of alpha-synuclein as a potential biomarker for the diagnosis and/or progression of PD. To assess the reliability of alpha-synuclein as a diagnostic marker, our ELISA methods will be refined so that we can reliably measure the levels of various forms of alpha-synuclein (e.g. total, oligomeric) in blood plasma samples. Blood samples will be collected from at least 300 cases of idiopathic PD and 600 neurological and non-neurological controls. Repeat blood samples will also be taken from some cases of PD for longitudinal studies to investigate if the levels of alpha-synuclein change progressively with the clinical course of the disease (to be monitored by clinical rating scales). These latter studies will determine if alpha-synuclein can be used as a surrogate marker for disease progression. This would be particularly useful for streamlining the testing of new drugs in clinical trials. This research will be carried out by a multi-disciplinary team involving neuroscientists, clinicians and statisticians/epidemiologists from Lancaster and Manchester Universities, and major clinical neuroscience units based in Manchester and Preston, in close collaboration with Zyentia, a small biotechnology company who specialise in the development of novel drugs for ?protein folding? disorders. As an integral part of the project, Zyentia will provide samples from animal models of PD for biomarker studies. They will also organise and fund a phase II clinical trial on one of their lead compounds, a novel inhibitor of alpha-synuclein aggregation, which will use alpha-synuclein as a surrogate marker for PD in combination with standard disease rating scales. It is expected that this trial will gauge the potential of alpha-synuclein as a surrogate biomarker for future clinical studies in PD, perhaps facilitating the development of new and improved therapies for this condition.