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O5‐10‐05: NOVEL INSIGHTS OF TAU RNA‐PROTEIN BIOLOGY IN THE PRECIPITATING ROLE OF CHRONIC STRESS ON ALZHEIMER'S DISEASE BRAIN PATHOLOGY
Author(s) -
Sotiropoulos Ioannis,
Silva Joana,
Rodrigues Sara,
Gomes Patricia,
Dioli Chrysoula,
Soares-Cunha Carina,
Takashima Akihiko,
Wolozin Benjamin,
Sousa Nuno
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.4892
Subject(s) - proteostasis , stress granule , autophagy , tau protein , microbiology and biotechnology , protein aggregation , pi3k/akt/mtor pathway , programmed cell death , biology , neurodegeneration , intracellular , neuroscience , neurotoxicity , unfolded protein response , chemistry , alzheimer's disease , disease , signal transduction , medicine , biochemistry , translation (biology) , endoplasmic reticulum , apoptosis , messenger rna , organic chemistry , toxicity , gene
conditions of AD brain in-vitro, we treated primary neuronal cultures with synthetic oligomeric Amyloid beta (Ab) and analyzed the effects of alterations in the levels of NSUN2 on tau proteostasis using a myriad of immunocytochemical and biochemical approaches. In addition, we chose Drosophila as our in-vivo model system to study NSUN2-microRNA modulation of tau neurotoxicity and behavior. Results: Our data supports dysregulation of NSUN2 in post-mortem brain tissue from AD patients when compared to healthy controls. In addition, we found that oligomeric Ab induces both dysregulation of NSUN2 and changes in tau proteostasis in primary neuronal cultures. Furthermore, bioinformatic analysis shows predicted methylation sites in miRNAs that have been implicated in AD. Strikingly, our in-vivo data shows that overexpression of NSUN2 can rescue tau induced toxicity. Conclusions: We propose that NSUN2 mediates methylation of brain miRNAs promoting alterations in tau proteostasis leading to neurodegeneration and cognitive dysfunction. Discovering the earliest events driving alterations in tau proteostasis will identify possible therapeutic targets to slow and/or halt the progression of the disease.