Alzheimer's disease (AD) is a progressive disorder that causes brain cells to degenerate and die. AD is one of the common causes of dementia that leads to a decline in thinking, behavioral and social skills that disrupts a person's ability to function independently. Tau-tubulin kinase1 (TTBK1) is a crucial disease regulating AD protein, which is majorly responsible for the phosphorylation and accumulation of tau protein at specific Serine/Threonine residues found in paired helical filaments, suggesting its role in tauopathy. TTBK1 involvement in many diseases and the restricted expression of TTBK1 to the central nervous system (CNS) makes TTBK1 an attractive therapeutic target for tauopathies. The genetic variations in TTBK1 are primarily involved in the TTBK1 pathogenesis. This study highlighted the destabilizing, damaging and deleterious effect of the mutation R142Q on TTBK1 structure through computational predictions and molecular dynamics simulations. The protein deviation, fluctuations, conformational dynamics, solvent accessibility, hydrogen bonding, and the residue-residue mapping confirmed the mutant effect to cause structural aberrations, suggesting overall destabilization due to the protein mutation. The presence of well-defined free energy minima was observed in TTBK1-wild type, as opposed to that in the R142Q mutant, reflecting structural deterioration. The overall findings from the study reveal that the presence of R142Q mutation on TTBK1 is responsible for the structural instability, leading to disruption of its biological functions. The mutation could be used as future diagnostic markers in treating AD.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/jcb.30112 | 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!