Association of the TBK1 mutation p.Ile334Thr with frontotemporal dementia and literature review

ConclusionWe proposed the TBK1 mutation p.Ile334Thr as a likely pathogenic variant in bvFTD which also expanded the clinical spectrum of this variant. It can partially abrogate TBK1 functions and be responsible for FTD ‐ALS spectrum diseases through neuroinflammatory pathway.
Source: Molecular Genetics & Genomic Medicine - Category: Genetics & Stem Cells Authors: Tags: ORIGINAL ARTICLE Source Type: research

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We describe two siblings with a novel OPTN mutation and atypical parkinsonian phenotype.
Source: Parkinsonism and Related Disorders - Category: Neurology Authors: Tags: Correspondence Source Type: research
AbstractOver the last two decades, a number of studies have underlined the importance of lysosomal ‐based degradative pathways in maintaining the homeostasis of post‐mitotic cells, and revealed the remarkable contribution of a functional autophagic machinery in the promotion of longevity. In contrast, defects in the clearance of organelles and aberrant protein aggregates have been linked to a ccelerated neuronal loss and neurological dysfunction. Several neurodegenerative disorders, among which Alzheimer disease (AD), Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) to name a few, are associated wi...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: Review Source Type: research
AbstractIn 2011, a hexanucleotide repeat expansion in the first intron of the C9orf72 gene was identified as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The proposed disease mechanisms include loss of C9orf72 function and gain of toxicity from the bidirectionally transcribed repeat-containing RNAs. Over the last few years, substantial progress has been made to determine the contribution of loss and gain of function in disease pathogenesis. The extensive body of molecular, cellular, animal, and human neuropathological studies is conflicted, but the predominance of ...
Source: Neurotherapeutics - Category: Neurology Source Type: research
Publication date: Available online 22 October 2019Source: Journal of Molecular BiologyAuthor(s): Owen Conway, Hafize Aysin Akpinar, Vladimir Rogov, Vladimir KirkinAbstractNeurons are electrically excitable, post-mitotic cells that perform sensory, relaying, and motor functions. Because of their unique morphological and functional specialization, cells of this type are sensitive to the stress caused by accumulation of misfolded proteins or damaged organelles. Autophagy is the fundamental mechanism that ensures sequestration of cytosolic material and its subsequent degradation in lysosomes of eukaryotic cells, thereby provid...
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research
Abstract Stress granules (SGs) are dynamic membraneless compartments composed out of RNA-binding proteins (RBPs) and RNA molecules that assemble temporarily to allow the cell to cope with cellular stress by stalling mRNA translation and moving synthesis towards cytoprotective proteins. Aberrant SGs have become prime suspects in the nucleation of toxic protein aggregation in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Perturbed SG dynamics appears to be mediated by alterations in RNA binding proteins (RBP). Indeed, a growing number of FTD and/or ALS related RBPs coding genes (TDP43, FUS, ...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
This study presents a novel method of targeted DNA methylation that utilizes endogenous DNA double strand break repair pathways and applies it to the neurodegenerative disease gene C9orf72. A double strand break induced by CRISPR/cas9 in the promoter of C9orf72 is sufficient to induce DNA methylation, and methylation can be precisely targeted through the process of homology directed repair (HDR) via delivery of an in vitro methylated exogenous repair template. Long methylated double stranded DNA templates induce more methylation than shorter templates and with higher efficiency than a dCas9-DNMT3a fusion protein construct....
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Methylation profiling by genome tiling array Homo sapiens Source Type: research
This study presents a novel method of targeted DNA methylation that utilizes endogenous DNA double strand break repair pathways and applies it to the neurodegenerative disease gene C9orf72. A double strand break induced by CRISPR/cas9 in the promoter of C9orf72 is sufficient to induce DNA methylation, and methylation can be precisely targeted through the process of homology directed repair (HDR) via delivery of an in vitro methylated exogenous repair template. Long methylated double stranded DNA templates induce more methylation than shorter templates and with higher efficiency than a dCas9-DNMT3a fusion protein construct....
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Methylation profiling by genome tiling array Homo sapiens Source Type: research
ConclusionsIn this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD.
Source: PLoS Medicine - Category: Internal Medicine Authors: Source Type: research
Publication date: Available online 3 October 2019Source: NeuronAuthor(s): Weiwei Cheng, Shaopeng Wang, Zhe Zhang, David W. Morgens, Lindsey R. Hayes, Soojin Lee, Bede Portz, Yongzhi Xie, Baotram V. Nguyen, Michael S. Haney, Shirui Yan, Daoyuan Dong, Alyssa N. Coyne, Junhua Yang, Fengfan Xian, Don W. Cleveland, Zhaozhu Qiu, Jeffrey D. Rothstein, James Shorter, Fen-Biao GaoSummaryHexanucleotide GGGGCC repeat expansion in C9ORF72 is the most prevalent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism is the aberrant accumulation of dipeptide repeat (DPR)...
Source: Neuron - Category: Neuroscience Source Type: research
Abstract p97, also known as valosin-containing protein or CDC48, is a member of the AAA+ protein family that is highly conserved in eukaryotes. It binds to various cofactors in the body to perform its protein-unfolding function and participates in DNA repair, degradation of subcellular membrane proteins, and protein quality control pathways, among other processes. Its malfunction can lead to many diseases, such as inclusion body myopathy, associated with Paget's disease of bone and/or frontotemporal dementia, amyotrophic lateral sclerosis disease, and others. In recent years, many small molecule inhibitors have be...
Source: Current Medicinal Chemistry - Category: Chemistry Authors: Tags: Curr Med Chem Source Type: research
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