Funded Studies
Objective/Rationale:
Parkinson’s disease is associated with the appearance of large, intracellular aggregates termed Lewy bodies consisting of damaged, truncated, aggregated and misfolded proteins. The large inclusions arise because the neurons are deluged by aggregates in Parkinson’s disease patients, and therefore the otherwise effective proteasomes cannot sufficiently eliminate the aggregates. Thus, over time, the aggregates lead to the death of dopaminergic neurons. The clearance deficiencies are thought to occur prior to the development of clinical symptoms. Detection of markers for inefficient protein degradation therefore holds promise for pre-clinical detection of Parkinson’s disease.
Project Description:
Inefficient protein degradation in the neurons will likely cause appearance of aberrantly cleaved proteins in cerebrospinal fluid. We have therefore developed a mass spectrometry-based screening method that can focus on and quantify Parkinson’s disease specific protein-termini in cerebrospinal fluid. Using this approach we have detected several markers that can differentiate non-neurodegenerative subjects from patients with clear-cut Parkinson’s disease. The aim of the current project is to use a highly sensitive quantitative mass spectrometric platform to assess the validity of the markers on an extensive panel of cerebrospinal fluid samples. Longitudinal studies will be performed to determine how the marker levels change during the course of the disease; in turn these will reveal whether the markers can be applied for early detection of Parkinson’s disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Typically, Parkinson’s disease is not diagnosed before 70 percent of the dopaminergic neurons have died which leaves little time for otherwise promising neuroprotective strategies. Therefore a strong need exists for new, robust biomarkers that can detect the early PD stages. These biomarkers will be indispensable in the design of new clinical trials aiming at testing novel disease-modifying neuroprotective strategies. Also the markers (if successful) will be valuable when testing new drugs for improved clearance of cytotoxic proteins.
Anticipated Outcome:
By this grant we expect to confirm the validity and applicability of the discovered biomarker leads by answering these questions:
Can the initial, promising findings be replicated in a new cohort?
Do the leads display the required specificity and sensitivity in order to be clinically relevant?
Do the markers track disease progression?
Do the markers provide early detection of Parkinson’s disease?