Analysis of ER and mitochondria dynamics and interaction during protein aggregation

• Grant number: 19/01290-9
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): April 01, 2019
• Effective date (End): May 31, 2021
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Acordo de Cooperação: Fundação para a Ciência e a Tecnologia (FCT)
• Principal Investigator: Merari de Fátima Ramires Ferrari
• Grantee: Seyed Reza Raeisossadati
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/07592-4 - The role of quality control mechanisms in the loss of proteostasis in age-dependent neurodegenerative diseases, AP.R

Abstract

Protein misfolding is a feature of normal aging process, however it is more pronounced in age-related neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. There are two biological hallmarks in Alzheimer's disease, the formation of extra-cellular beta-amyloid peptide plaques and the intracellular deposition of tau protein tangles. Alpha-synuclein is the protein linked to both sporadic and early-onset Parkinson's disease and is the main component of the Lewy bodies found in the cytoplasm of dopaminergic cells in patients. Although the mechanism underlying protein accumulation remains unclear, it is believed that impaired quality control mechanisms can trigger downstream pathogenic events, leading to neurodegeneration of different subset of neurons. In fact, neurons rely on elaborated pathways of protein quality control and removal to maintain intracellular protein homeostasis. Interestingly, neurodegeneration resulting from impaired quality control mechanisms is often accompanied by mitochondrial dysfunction and endoplasmatic reticulum stress that are known to be present in both diseases. We plan to investigate how protein misfolding leads to mitochondrial damage and endoplasmatic reticulum stress. Caloric restriction activates bulk autophagy allowing the degradation of defective organelles, namely mitochondria and endoplasmic reticulum, and protein aggregates. Dopaminergic neurons derived from iPS of PD patients and primary cultures of hippocampal neurons from AD transgenic mice will be subjected to the analysis of intracellular dynamics, trafficking and cross-talk between ER and Mitochondria. Live cell imaging will be employed to detect mitochondrial and autophagic vacuoles movement, microtubules-dependent ER movements, ER-mitochondria interaction and transfer of calcium between the ER and mitochondria. We will also evaluate the effects of starvation on protein aggregation, by Western Blot of alpha-synuclein, mitochondrial and ER function, dynamics, trafficking and cross-talk in iPS-derived neurons and neurons from AD transgenic mice. (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)

RAEISOSSADATI, REZA; FERRARI, MERARI F. R.. Mitochondria-ER Tethering in Neurodegenerative Diseases. Cellular and Molecular Neurobiology, NOV 2020. (13/08028-1, 18/07592-4, 19/01290-9)

RAEISOSSADATI, REZA; FERRARI, MERARI F. R.; KIHARA, ALEXANDRE HIROAKI; ALDIRI, ISSAM; GROSS, JEFFREY M.. Epigenetic regulation of retinal development. EPIGENETICS & CHROMATIN, v. 14, n. 1, DEC 9 2021. (18/07592-4, 19/01290-9)