Receptor tyrosine kinase ROR1 ameliorates A\u03b21\u201342 induced cytoskeletal instability and is regulated by the miR146a-NEAT1 nexus in Alzheimer\u2019s disease

Kaushik Chanda,Debashis Mukhopadhyay,Nihar Ranjan Jana

doi:10.1038/s41598-021-98882-0

Abstract

Alzheimer’s disease (AD) involves severe cytoskeletal degradation and microtubule disruption. Here, we studied the altered dynamics of ROR1, a Receptor Tyrosine Kinase (RTK), and how it could counter these abnormalities. We found that in an Aβ1–42 treated cell model of AD, ROR1 was significantly decreased. Over expressed ROR1 led to the abrogation of cytoskeletal protein degradation, even in the presence of Aβ1–42, preserved the actin network, altered actin dynamics and promoted neuritogenesis. Bioinformatically predicted miRNAs hsa-miR-146a and 34a were strongly up regulated in the cell model and their over expression repressed ROR1. LncRNA NEAT1, an interactor of these miRNAs, was elevated in mice AD brain and cell model concordantly. RNA Immunoprecipitation confirmed a physical interaction between the miRNAs and NEAT1. Intuitively, a transient knock down of NEAT1 increased their levels. To our knowledge, this is the first instance which implicates ROR1 in AD and proposes its role in preserving the cytoskeleton. The signalling modalities are uniquely analyzed from the regulatory perspectives with miR-146a and miR-34a repressing ROR1 and in turn getting regulated by NEAT1.

Highlights

Alzheimer’s disease (AD) is characterised by a gradual and continuous loss of memory retention and cognition
Besides Aβ oligomers, Receptor Tyrosine Kinase (RTK) signalling and miRNA mediated regulations, an emerging subset of long noncoding RNAs have been implicated in governing the cytoskeleton. lncRNA Down-regulated in hepatocellular carcinoma (Dreh) regulates vimentin, changing the cytoskeleton structure and cell morphology in cancer cells[25,26]
We looked at the deregulated levels of ROR1, both at the transcript and protein levels in SHSY-5Y cells treated with Aβ1–42 and compared with DMSO control

Summary

Introduction

Alzheimer’s disease (AD) is characterised by a gradual and continuous loss of memory retention and cognition. Several studies have implicated the specific role of Aβ in disrupting the normal cytoskeleton by affecting the Amyloid Precursor Protein (APP) trafficking, altering the filamentous actin ratio and changing the epigenetic signatures of microtubule p roteins[5,6]. Several other miRNAs target key proteins in AD, like miR-106a, miR-106b, miR-520c, miR-101 and miR-153 directly target Amyloid Precursor Protein and control Aβ levels; miR-29a/b/c, miR-107, miR-195 and miR-124 targets BACE1, thereby regulating the intramembrane cleavage of APP; miR-132 targets Tau; miR-34a targets TREM2 and miR-146a targets a critical component of actin modulator, ROCK122. Besides Aβ oligomers, RTK signalling and miRNA mediated regulations, an emerging subset of long noncoding RNAs (lncRNAs) have been implicated in governing the cytoskeleton. The exact mechanism of action is unknown, research suggests that interaction of NEAT1 with associated miRNAs could be one paradigm which governs disease pathology. Such regulatory networks have been reported involving NEAT1 in Alzheimer’s disease as w ell[50,51], but the knowledge is rudimentary

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