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Characterization of the molecular mechanisms used by Arc protein to modify the intracellular traffic and processing of AMPA receptors and beta-amyloid precursor protein (APP)

Grant number: 17/12022-0
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): September 01, 2017
Effective date (End): May 04, 2021
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal Investigator:Luis Lamberti Pinto da Silva
Grantee:Yunan Costa Januário
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The activity-regulated cytoskeleton-associated protein (Arc) has its expression induced in neurons that exhibit high synaptic activity and is essential for the modulation of synaptic transmission. One of the effects of Arc in this process is to accelerate AMPA receptor (AMPAR) endocytosis in dendritic spines, downregulating the synaptic activity mediated by these receptors. Recently our research group has demonstrated that Arc interacts with the AP2 adaptor complex which is a key molecule in clathrin mediated endocytosis and this interaction is essential to Arc's action of inducing endocytosis of AMPAR. In the present work we propose to extend these studies investigating whether Arc induces the targeting of endocytosed AMPAR for lysosomal degradation and to analyze the molecular mechanism involved in this process. Other works also suggest that Arc alters the subcellular localization of beta-amyloid Precursor Protein (APP) and induces the generation of the neurotoxic beta-amyloid peptide, an important process for triggering Alzheimer's disease. Pilot experiments performed by our group allowed us to identify that Arc interacts with another member of the adaptor family, the AP4 complex. These results allowed us to determine the subunit of AP4 that mediates interaction with Arc as well the Arc region involved in this interaction. Considering that AP4 is known to be involved in modulating intracellular APP traffic, another objective of this work will be to investigate whether Arc modulates the amyloidogenic processing of APP through its interaction with AP4. Thus, this research project seeks to elucidate how synaptic activity interferes with the intracellular traffic of AMPAR and APP, through the ability of the Arc protein to interact with members of the family of adaptive complexes, regulating their function. (AU)

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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)
TAVARES, LUCAS A.; JANUARIO, YUNAN C.; DASILVA, LUIS L. P.. HIV-1 Hijacking of Host ATPases and GTPases That Control Protein Trafficking. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, . (17/12022-0, 18/00297-7, 16/18207-9)
JANUARIO, YUNAN C.; DASILVA, LUIS L. P.. Hijacking of endocytosis by HIV-1 Nef is becoming crystal clear. NATURE STRUCTURAL & MOLECULAR BIOLOGY, v. 27, n. 9, p. 3-pg., . (18/00297-7, 17/12022-0, 19/02418-9)
JANUARIO, YUNAN C.; EDEN, JESSICA; DE OLIVEIRA, LUAN S.; DE PACE, RAFFAELLA; TAVARES, LUCAS A.; DA SILVA-JANUARIO, MARA E.; APOLLONI, VINICIUS B.; WILBY, ELISE L.; ALTMEYER, RANDOLF; BURGOS, PATRICIA, V; et al. Clathrin adaptor AP-1-mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments. Journal of Biological Chemistry, v. 298, n. 8, p. 19-pg., . (19/08461-3, 17/18477-9, 21/01182-1, 17/12022-0, 18/00297-7, 20/08831-2)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
JANUÁRIO, Yunan Costa. Functional characterization of AP-1 and Arc/Arg3.1 in the transport and processing of APP at the late secretory pathway. 2021. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.

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