Influence of calcium and MIRO proteins upon mitochondria transport in human neurons derived from induced pluripotent stem cells from Alzheimer's patients

• Grant number: 13/18028-9
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: January 13, 2014
• End date: December 12, 2014
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Merari de Fátima Ramires Ferrari
• Grantee: Rodrigo dos Santos Chaves
• Supervisor: Lawrence S. B. Goldstein
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of California, San Diego (UC San Diego), United States
• Associated to the scholarship: 11/00478-2 - Influence of calcium and MIRO proteins on mitochondrial mobility before and during protein aggregation involved in neurodegeneration, BP.DD

Abstract

Most cases of Alzheimer's disease (AD) are sporadic (sAD), therefore a small fraction (5%) of AD is familial (fAD) due to the inheritance of mutated genes. Mutations in presenilin genes (PS1 and PS2) account for 40% of AD familial cases. The most severe mutation in PS1 is a donor-acceptor splice mutation that causes two amino-acid substitutions and an in-frame deletion of exon 9 (PS1-”E9), which trigger the overproduction of beta amyloid (A²) triggering the formation of A² oligomers and increase Ca2+ intracellular concentrations. Evidences demonstrated that increase in Ca2+ levels could impair mitochondria transport though a specific process dependent of miro EF hand domain and impairment of mitochondria transport has been implicated in early dysfunctions associated with AD neurophatology. Here we hypothesized that disruption of mitochondria transport could be triggered by increase in Ca2+ intracellular concentration, promoting protein aggregation and neurodegeneration in AD. Our group identified evidences supporting the Ca2+ hypothesis in cell cultures of Lewis rats exposed to rotenone. The next step is the confirmation of the relation between Ca2+ and the miro proteins for mitochondrial trafficking in human cells including the genetic background for AD. In the light of this, the present study aims to evaluate miro-1, Ca2+ levels, mitochondria transport and protein aggregates in neurons derived from induced pluripotent stem cell (iPSC) of fibroblasts from fAD patients carrying PS1-”E9, sAD patients and non-demented controls. (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)

FONG, LAUREN K.; YANG, MAX M.; CHAVES, RODRIGO DOS SANTOS; REYNA, SOL M.; LANGNESS, VANESSA F.; WOODRUFF, GRACE; ROBERTS, ELIZABETH A.; YOUNG, JESSICA E.; GOLDSTEIN, LAWRENCE S. B.. Full-length amyloid precursor protein regulates lipoprotein metabolism and amyloid- clearance in human astrocytes. Journal of Biological Chemistry, v. 293, n. 29, p. 11341-11357, JUL 20 2018. (13/18028-9)