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O4‐07‐04: SUMOylation connections to plaque and tangle pathology
Author(s) -
Matsuzaki Shinsuke,
Fraser Paul,
Yamada Kohei,
St GeorgeHyslop Nicola,
Katayama Taiichi,
Tohyama Masaya,
Raught Brian
Publication year - 2012
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.2012.05.1674
Subject(s) - sumo protein , immunoprecipitation , microbiology and biotechnology , transgene , biology , subcellular localization , proteomics , ubiquitin , amyloid (mycology) , genetically modified mouse , chemistry , biochemistry , cell culture , cytoplasm , genetics , gene , botany
ing mice, brain tissues, and primary neuronal cultures, we examined neuronal apoptosis (TUNEL), synaptic integrity (synaptophysin synapsin I, & PSD95), gliosis (GFAP & Iba-1), and learning & memory. In addition, in transfected hippocampal HT22 cells and primary neurons, we tested whether the RanBP9-cofilin pathway underlies Abeta1-42 induced neurotoxicity using Annexin V / Propidium iodide staining and lactate dyhydrongenase (LDH) release assays. Results: Here we show that RanBP9 protein levels are increased by 4-fold in FAD mutant APP transgenic mice. Accordingly, RanBP9 transgenic mice demonstrate significantly increased synapse loss,neurodegeneration, gliosis, and spatial memory deficits. RanBP9 overexpression promotes apoptosis and potentiates Aß-induced neurotoxicity independent of its capacity to promote Abgeneration. Conversely, RanBP9 reduction by siRNA in HT22 cells or gene dosage in RanBP9+/neurons mitigates Ab-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin in both HT22 cells and primary neurons, a key regulator of actin dynamics and mitochondriamediated apoptosis, and siRNA knockdown of cofilin abolished both Aß and RanBP9-induced apoptosis. Conclusions: These findings are the first to demonstrate that the RanBP9-cofilin pathway plays a key role not only in Aß generation and cytoskeletal aberrations but also in mediating Aß -induced neurotoxicity.