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Synapse to nuclear information transmission by presenilin1-cleavage of PTPRT is undermined in Alzheimer’s disease

ABSTRACT: PTPRT (receptor-type tyrosine-protein phosphatase T), as a brain-specific type 1 transmembrane protein, plays important function in neurodevelopment and synapse formation. Here, we report that the downregulated levels of Ptprt mRNA and protein is found in both human AD and APP/PS1 mouse brains. We further identified that PTPRT intracellular domain (ICD), which was released by ADAM10- and g-secretase-dependent cleavage of PTPRT, efficiently translocated to the nucleus via a conserved nuclear localization signal. RNA sequencing reveals that expression of the PICD alone can profoundly alter the expression of genes associated with synapse function and dephosphorylation, phosphatase and cell adhesion. Inhibition of nuclear-localization of PICD via the mutation of its nuclear localization signal (NLS) leads to accumulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3), which is a substrate of PTPRT and eventually resulted in neuronal cell death. AVV1-PICD in vitro and in vivo robustly decreases the levels of phosph-STAT3(Y705) in APP/PS1 neurons, attenuates Ab pathology, and improves synaptic function and behavioral deficits in APP/PS1 mice. Our findings define a novel role of decreased PTPRT and its nuclear ICD fragment in the events promote AD pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE159943 | GEO | 2022/10/23

REPOSITORIES: GEO

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Synapse to nuclear information transmission by presenilin1-cleavage of PTPRT is undermined in Alzheimer’s disease

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