As the most common neurodegenerative disease, Alzheimer's disease (AD) is characterized by memory, perception, and behavioral damage, which may ultimately lead to emotional fluctuation and even lethal delirium. Increasing studies indicate that microRNAs (miRNAs) are associated with pathological features of AD. However, the role of miR-219-5p in AD progression is still unclear. In this study, the functions of miR-219-5p were analyzed in vitro and in vivo. miR-219-5p was notably overexpressed in brain tissues of patients with AD. The overexpression of miR-219-5p activated the phosphorylation of Tau-Ser198, Tau-Ser199, Tau-Ser201, and Tau-Ser422. We further showed that miR-219-5p could mediate a decrease in the protein levels of tau-tubulin kinase 1 (TTBK1) and glycogen synthase kinase 3β (GSK-3β) by directly binding to their 3'-untranslated region, thereby promoting the phosphorylation of tau in SH-SY5Y Cells. Rescue experiments further revealed that the phosphorylation of tau-mediated by miR-219-5p was dependent on the inhibition of TTBK1 and GSK-3β. Moreover, suppressing the expression of both TTBK1 and GSK-3β using miR-219-5p remarkably rescued AD-like symptoms in amyloid precursor protein/presenilin 1 mice. Our findings indicate that the upregulation of TTBK1 and GSK-3β mediated by the loss of miR-219-5p is a possible mechanism that contributes to tau phosphorylation and AD progression.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/jcb.28276 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Targeted protein degradation with bifunctional molecules as a novel therapeutic modality for Alzheimer's disease & beyond.
Neurotherapeutics
December 2024
Department of Neurology, Precision Therapeutics Unit, Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address:
Alzheimer's disease (AD) is associated with memory and cognitive impairment caused by progressive degeneration of neurons. The events leading to neuronal death are associated with the accumulation of aggregating proteins in neurons and glia of the affected brain regions, in particular extracellular deposition of amyloid plaques and intracellular formation of tau neurofibrillary tangles. Moreover, the accumulation of pathological tau proteoforms in the brain concurring with disease progression is a key feature of multiple neurodegenerative diseases, called tauopathies, like frontotemporal dementia (FTD) where autosomal dominant mutations in the tau encoding MAPT gene provide clear evidence of a causal role for tau dysfunction.
View Article and Find Full Text PDFComputational Design of Novel Tau-Tubulin Kinase 1 Inhibitors for Neurodegenerative Diseases.
Pharmaceuticals (Basel)
July 2024
Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
The tau-tubulin kinase 1 (TTBK1) protein is a casein kinase 1 superfamily member located at chromosome 6p21.1. It is expressed explicitly in the brain, particularly in the cytoplasm of cortical and hippocampal neurons.
View Article and Find Full Text PDFComputational identification of potential tau tubulin kinase 1 (TTBK1) inhibitors: a structural analog approach.
In Silico Pharmacol
July 2024
School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632014 India.
Unlabelled: Abnormal deposition or aggregation of protein alpha-synuclein and tau in the brain leads to neurodegenerative disorders. Excessive hyperphosphorylation of tau protein and aggregations destroys the microtubule structure resulting in neurofibrillary tangles in neurons and affecting cytoskeleton structure, mitochondrial axonal transport, and loss of synapses in neuronal cells. Tau tubulin kinase 1 (TTBK1), a specific neuronal kinase is a potential therapeutic target for neurodegenerative disorders as it is involved in hyperphosphorylation and aggregation of tau protein.
View Article and Find Full Text PDFCK1δ/ε kinases regulate TDP-43 phosphorylation and are therapeutic targets for ALS-related TDP-43 hyperphosphorylation.
Neurobiol Dis
June 2024
Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0624, USA. Electronic address:
Hyperphosphorylated TAR DNA-binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons is the neuropathological hallmark of amyotrophic lateral sclerosis (ALS) and a group of neurodegenerative diseases collectively referred to as TDP-43 proteinopathies that includes frontotemporal dementia, Alzheimer's disease, and limbic onset age-related TDP-43 encephalopathy. The mechanism of TDP-43 phosphorylation is poorly understood. Previously we reported casein kinase 1 epsilon gene (CSNK1E gene encoding CK1ε protein) as being tightly correlated with phosphorylated TDP-43 (pTDP-43) pathology.
View Article and Find Full Text PDFCorrection to: Liraglutide versus pramlintide in protecting against cognitive function impairment through affecting PI3K/AKT/GSK‑3β/TTBK1 pathway and decreasing Tau hyperphosphorylation in high‑fat dietstreptozocin rat model.
Pflugers Arch
May 2024
Department of Physiology, Faculty of Medicine, Sohag University, Sohag, 82524, Egypt.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!