Atypical parkinsonism: a genomic, proteomic and metabolomic approach of Progressive Supranuclear Palsy

Abstract

Progressive supranuclear palsy (PSP) is a neurodegenerative disease which is part of the parkinsonian syndromes spectrum, together with idiopathic Parkinson's disease (PD), the most common of them. In the initial phases, the differential diagnosis between PD and other parkinsonian syndromes (also called atypical parkinsonism) can be challenging, due to the similarity of the symptoms and the lack of biomarkers to distinguish among these syndromes. Parkinsonian syndromes are highly disabling, with no cure. All of them lead to progressive neurodegeneration and to protein aggregates in the brain (alpha synuclein -synucleinpathies or Tau- tauopathies). The molecular bases that lead to dysfunction in protein metabolism and abnormal responses to oxidative stress are highly unknown. Tauopathies such as PSP, Alzheimer's disease, frontotemporal dementia and corticobasal degeneration differ not only in clinical aspects, but also in the type of Tau isoforms and brain regions which are mainly compromised. Recent data suggest that Tau oligomers are toxic and propagate in the central nervous system through a cell to cell seeding mechanism. The precise role of these oligomers and what are the other proteins involved in the neurodegenerative process must be elucidated. Induced pluripotent stem cells (iPSC) derived from the patients' somatic cells are a powerful toll to study pathophysiology; using these tools together with other functional studies will provide more knowledge into the neurodegenerative process. Objectives: the aim of this study is to develop iPSC derived from skin fibroblasts of patients with PSP and controls, and further differentiate them into neuronal progenitors (NPC) and astrocytes. With this model, we will be studying the transcriptome, proteome and metabolome, in other to identify biomarkers and other molecules that could be the target of modulation to prevent neurodegeneration. Methods: skin fibroblasts from PSP patients and controls with be reprogrammed into iPSC with episomal vectors. Then, they will be differentiated into NPC and astrocytes. These cells will have their transcriptome screened through RNAseq. The secretome and cell protein profile will be studied through high resolution mass spectrometry using metabolomics and proteomics approaches. Expected results: we aim to develop iPSC from patients with PSP, that will be available for future studies, such as drug screening. Besides, we expect to identify biomarkers and other molecules that may be modulated in order to control the neurodegenerative process. (AU)