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Gene expression study of MAPT isoforms in astrocytes generated from induced pluripotent stem cells derived from fibroblasts of patients with progressive supranuclear paralysis and healthy controls

Grant number: 19/14707-5
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): September 01, 2019
Effective date (End): August 31, 2020
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Patrícia Maria de Carvalho Aguiar
Grantee:Lais Lins de Lira
Home Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil

Abstract

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disease which is part of the spectrum of parkinsonian syndromes, together with other conditions, such as idiopathic Parkinson's disease (PD), the most common of these. All lead to progressive neurodegeneration and, ultimately, pathological protein aggregates of alpha-synuclein (synucleinopathies) or Tau (tauopathies) in the central nervous system (CNS). The pathophysiological molecular bases that lead to these dysfunctions in the protein metabolism and the response to oxidative stress are still poorly understood. The gene MAPT encodes the TAU protein and has 6 transcripts; its H1 haplotype is a risk factor for neurodegeneration. In PSP, there is an imbalance in between transcripts containing or not the exon 10 (4R and 3R isoforms, respectively), with a predominance of the 4R isoform in the CNS. Due to the difficulties in accessing brain tissue in vivo, it is necessary to invest in less invasive methods for understanding the pathophysiological process. The development of induced pluripotent stem cells (iPSC) from peripheral tissue of patients is an important tool for the study of various diseases. The use of this tool, together with other functional studies, may help in the identification of biomarkers and new therapeutic targets. In the case of PSP, it is necessary to investigate whether the model of neural lines derived from iPSC are able to reproduce the unbalance of MAPT isoforms found in patients' brains. Aims: To develop a neural lineage model from iPSCs derived from patients with PSP to verify whether MAPT isoforms in this model reproduce the same unbalance found in the brain of patients with PSP. Methods: skin fibroblasts from patients with PSP and normal controls will be reprogrammed iPSC with episomal vectors and, later, for neural precursors and astrocytes. The proportion of the gene expression of MAPT 3R and 4R isoforms will be investigated in astrocytes, comparing early passages with older passages, through quantitative PCR in real time. Expected results: we will define whether the proportion of MAPT gene isoforms expressed in the astrocytes changes over the course of aging which may have implications for the use of this model to study PSP.