Laboratory of Biochemistry and Functional Proteomics
Summary of Research Activities
Diagnosis of Parkinson's disease is currently based on the clinical evaluation of extrapyramidal signs, such as tremor, rigidity and bradykinesia, when the degeneration of dopaminergic nigral neurons has raised over 70%. The identification of specific biomarkers is critical for the early diagnosis of the disease and also to monitor its progression. Additionally, the assessment of disease-modifying drugs requires the identification of early-stage patients to be included in clinical studies. Non-motor signs frequently precede the onset of PD but they may be unspecific, whereas instrumental investigations are characterized by high cost and use of radioactive tracers that hamper their application population-wide. Molecular biomarkers in body fluids are likely to meet the expectation of unprecedented specificity, in particular when a panel of biomarkers is concerned, together with costs that are lower than those of imaging/functional biomarkers.
We found out that the levels of 20 proteins in peripheral blood are significantly different in Parkinson's disease patients with respect to control subjects. These results have been obtained through an unbiased proteomics biomarkers discovery. A predictive function may be calculated as a linear combination of the measured levels in order to classify affected subjects and to assign a progression score. Each of the enrolled subjects has been iteratively excluded from the cohort and independently classified. In this way, sensitivity = 100% and specificity = 94% were calculated. The research group is looking for partners in order to jointly develop a clinical assay for the early, preclinical diagnosis of Parkinson's disease based on the measurement of peripheral blood proteins (WIPO Patent Appl. pending).
Parkinson's disease is the most common neurodegenerative movement disorder, affecting about 6 million people worldwide with a slow progression of the symptoms. Its prevalence is expected to double in the most populated areas within the next two decades, according to increasing aged population. Consequently, Parkinson's disease is a socio-economic trouble and a major challenge for the public health system. Parkinson's disease treatment is merely symptomatic, as clinical symptoms appear when about 70% of the involved neurons are lost and potential disease-modifying/neuroprotective therapies would have no effect. In turn, the availability of an objective measure that allows early diagnosis would strongly impact on the costs that biotech- and pharma-companies will sustain in order to develop disease-modifying therapies. The establishment of suitable models to investigate the mechanisms of Parkinson's disease progression and, on the other hand, the discovery and validation of selective and specific molecular biomarkers for early and differential diagnosis are indeed two important goals for a better management of the disease. In this context, we focus on cellular and animal models of Parkinson's disease by describing their advantages and limitations as useful tools to identify pathogenetic pathways that deserve further exploitation. In parallel, we investigate how proteomics may provide a potent tool to observe altered pathways in models or altered biomarkers in patients with an unbiased, hypothesis-free approach.
Human serum albumin (HSA), the most abundant protein in plasma, is a monomeric multidomain macromolecule, representing the main determinant of plasma oncotic pressure and the main modulator of fluid distribution between body compartments. HSA displays an extraordinary ligand binding capacity, providing a depot and carrier for many endogenous and exogenous compounds. Indeed, HSA represents the main carrier for fatty acids, affects pharmacokinetics of many drugs, provides the metabolic modification of some ligands, renders potential toxins harmless, accounts for most of the anti-oxidant capacity of human plasma, and displays (pseudo-)enzymatic properties. HSA is a valuable biomarker of many diseases, including cancer, rheumatoid arthritis, ischemia, post-menopausal obesity, severe acute graft-versus-host disease, and diseases that need monitoring of the glycemic control. Moreover, HSA is widely used clinically to treat several diseases, including hypovolemia, shock, burns, surgical blood loss, trauma, hemorrhage, cardiopulmonary bypass, acute respiratory distress syndrome, hemodialysis, acute liver failure, chronic liver disease, nutrition support, resuscitation, and hypoalbuminemia. Recently, biotechnological applications of HSA, including implantable biomaterials, surgical adhesives and sealants, biochromatography, ligand trapping, and fusion proteins, have been reported.