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The role of quality control mechanisms in the loss of proteostasis in age-dependent neurodegenerative diseases

Grant number: 18/07592-4
Support Opportunities:Regular Research Grants
Duration: September 01, 2018 - August 31, 2022
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Convênio/Acordo: Fundação para a Ciência e a Tecnologia (FCT)
Principal Investigator:Merari de Fátima Ramires Ferrari
Grantee:Merari de Fátima Ramires Ferrari
Principal researcher abroad: Ana Raquel Fernandes Esteves
Institution abroad: Universidade de Coimbra (UC), Portugal
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):19/01290-9 - Analysis of ER and mitochondria dynamics and interaction during protein aggregation, BP.PD


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 ²-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. The present proposal aims to combine efforts, scientific and technical background from two teams in order to investigate how protein misfolding and quality control mechanisms (specifically autophagy) are compromised in both Alzheimer's and Parkinson's disease. Moreover we plan to investigate how protein misfolding leads to mitochondrial damage and endoplasmatic reticulum stress.Physical exercise training and caloric restriction seem to protect individuals against cognitive decline associated with physiological aging. Physical exercise can activate mitochondrial biogenesis, which will increase mitochondrial pool and improve total mitochondrial function. Caloric restriction activates bulk autophagy allowing the degradation of defective organelles, namely mitochondria and endoplasmic reticulum, and protein aggregates. Such approaches may have therapeutic value in overcoming the deleterious effects of aging and protecting the brain against age-associated neurodegenerative processes. Taking this into account we intend to evaluate how these non-invasive strategies will counteract many of the pathological alterations that characterize both neurodegenerative diseases. Overall, the purpose of the present study is to evaluate protein quality control systems in in vivo and in vitro models of aging and neurodegeneration, as well as, in brain samples from patients with Parkinson's or Alzheimer's disease. Furthermore, we aim to revert proteostasis loss focusing in physical exercise and caloric restriction as therapeutic strategies. Our proposal is groundbreaking, imperative and combines strengths from two groups that have scientific and methodological expertise in these areas of study. (AU)

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Scientific publications (8)
(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.; KIHARA, ALEXANDRE HIROAKI; ALDIRI, ISSAM; GROSS, JEFFREY M.. Epigenetic regulation of retinal development. EPIGENETICS & CHROMATIN, v. 14, n. 1, . (18/07592-4, 19/01290-9)
SEMEANO, ANA T.; TOFOLI, FABIANO A.; CORREA-VELLOSO, JULIANA C.; DE JESUS SANTOS, ANA P.; OLIVEIRA-GIACOMELLI, AGATHA; CARDOSO, RAFAELA R.; PESSOA, MATEUS A.; DA ROCHA, EDROALDO LUMMERTZ; RIBEIRO, GUSTAVO; FERRARI, MERARI F. R.; et al. Effects of Magnetite Nanoparticles and Static Magnetic Field on Neural Differentiation of Pluripotent Stem Cells. STEM CELL REVIEWS AND REPORTS, v. 18, n. 4, p. 18-pg., . (18/07366-4, 19/26852-0, 16/14513-8, 13/08028-1, 18/07592-4, 13/08135-2)
LIMA, RAQUEL S.; CARRETTIERO, DANIEL C.; FERRARI, MERARI F. R.. BAG2 prevents Tau hyperphosphorylation and increases p62/SQSTM1 in cell models of neurodegeneration. MOLECULAR BIOLOGY REPORTS, v. N/A, p. 13-pg., . (11/06434-7, 13/08028-1, 18/07592-4, 17/24722-6, 16/04409-9)
HENRIQUE, ALAN M.; GIANETTI, NATHALIA G.; FERRARI, MERARI F. R.. Parkin is downregulated among autophagy-related proteins prior to hyperphosphorylation of Tau in TS65DN mice. Biochemical and Biophysical Research Communications, v. 561, p. 59-64, . (13/08028-1, 18/11946-6, 18/07592-4)
MELO, THAIANY Q.; PALMA, FLAVIO R.; GOMES, FERNANDO; NETTO, LUIS E. S.; FERRARI, MERARI F. R.. Absence of Gem1 (mammalian Miro/Rhot) mitigates alpha-synuclein toxicity in a yeast model of Parkinson's disease. Molecular and Cellular Neuroscience, v. 122, p. 9-pg., . (13/08028-1, 11/06434-7, 15/18961-2, 18/07592-4)
RAEISOSSADATI, REZA; FERRARI, MERARI F. R.. Mitochondria-ER Tethering in Neurodegenerative Diseases. Cellular and Molecular Neurobiology, v. 42, n. 4, p. 14-pg., . (13/08028-1, 18/07592-4, 19/01290-9)
RAEISOSSADATI, REZA; FERRARI, MERARI F. R.. Mitochondria-ER Tethering in Neurodegenerative Diseases. Cellular and Molecular Neurobiology, . (13/08028-1, 18/07592-4, 19/01290-9)
CHAVES, JULIANA C. S.; MACHADO, FELIPPE T.; ALMEIDA, MICHAEL F.; BACOVSKY, TATIANA B.; FERRARI, MERARI F. R.. microRNAs expression correlates with levels of APP, DYRK1A, hyperphosphorylated Tau and BDNF in the hippocampus of a mouse model for Down syndrome during ageing. Neuroscience Letters, v. 714, . (18/07592-4, 15/18961-2, 15/10892-1)

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