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Mitochondria trafficking and autophagy in human dopaminergic neurons derived from embryonic and induced-pluripotent stem cells

Grant number: 12/15495-2
Support type:Regular Research Grants
Duration: May 01, 2013 - April 30, 2015
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Merari de Fátima Ramires Ferrari
Grantee:Merari de Fátima Ramires Ferrari
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Loss of dopaminergic neurons and protein aggregates containing alpha-synuclein are the meain cellular features of Parkinson's disease. However, cellular impairment is presente even before these aggregates, which may be of relevance to cell death. Stem cells are good models to study neurodegenerative diseases. Induced-pluripotent stem cells also allow the investigation of cellular functions in individuals affected by neurodegenerative diseases. In view of this, the objectives of the presente study are: implement the technique of derivation of dopaminergic neurons from embryonic stem cells and from fibroblasts; study the influence of calcium during the early phase of neurodegeneration, as well as evaluate mitochondria trafficking and the autophagy system in these neurons in the presence and absence of alfa-synculein aggregates. To this end, human embryonic stem cell and fibroblasts induced to pluripotency, by the expression of SOX2, c-MYC, OCT4 and KFL4, of patients diagnosed with idiopathic Parkinson's disease will be cultivated. Stem cells will be differentiated into dopaminergic neurons and submitted to fura-2 calcium labeling, expression of alpha-synuclein and mutant miro, as well as activation and repression of autophagy in order to comprehend some of the major cellular events occuring during the initial phase of dopaminegic neurodegeneration. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FARIZATTO, KAREN L. G.; IKONNE, UZOMA S.; ALMEIDA, MICHAEL F.; FERRARI, MERARI F. R.; BAHR, BEN A. A beta(42)-mediated proteasome inhibition and associated tau pathology in hippocampus are governed by a lysosomal response involving cathepsin B: Evidence for protective crosstalk between protein clearance pathways. PLoS One, v. 12, n. 8 AUG 10 2017. Web of Science Citations: 10.
MELO, T. Q.; VAN ZOMEREN, K. C.; FERRARI, M. F. R.; BODDEKE, H. W. G. M.; COPRAY, J. C. V. M. Impairment of mitochondria dynamics by human A53T alpha-synuclein and rescue by NAP (davunetide) in a cell model for Parkinson's disease. Experimental Brain Research, v. 235, n. 3, p. 731-742, MAR 2017. Web of Science Citations: 9.

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