Association between TBK1 mutations and risk of amyotrophic lateral sclerosis/frontotemporal dementia spectrum: a meta-analysis

AbstractRecently, mutations inTBK1 (TANK-binding kinase 1) have been reported to be a cause of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum, but the relationship between them remains unclear owing to the small sample size and low mutation rate. Therefore, we performed a two-stage meta-analysis to investigate the frequency ofTBK1 mutations in ALS/FTD patients and the association between the mutations and risk of ALS/FTD spectrum. In the first stage, 12 studies involving 4173 ALS/FTD patients were included. The frequencies of loss of function (LoF) and missense mutations were 1.0% (95% CI 0.6 –1.7%) and 1.8% (95% CI 0.9–3.4%) in ALS/FTD patients respectively. Subgroup analysis suggested a higher prevalence ofTBK1 mutations in European patients than that in Asian patients. In the second stage, 7 studies involving 3146 cases and 4856 controls were enrolled. Results showed thatTBK1 LoF mutations were associated with a significant increased risk for ALS/FTD spectrum (OR 11.78; 95% CI 4.21 –33.00;p 
Source: Neurological Sciences - Category: Neurology Source Type: research

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How hexanucleotide GGGGCC (G4C2) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G4C2 repeats. The expression of green fluorescent protein–conjugated (PR)50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, an...
Source: ScienceNOW - Category: Science Authors: Tags: Medicine, Diseases, Online Only r-articles Source Type: news
Publication date: Available online 11 February 2019Source: Journal of Molecular BiologyAuthor(s): Henriette Haukedal, Kristine FreudeAbstractAmyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD) are neurodegenerative disorders with clear similarities regarding their clinical, genetic and pathological features. Both are progressive, lethal disorders, with no current curative treatment available. Several genes correlated with ALS and FTD are implicated in the same molecular pathways. Strikingly, many of these genes are not exclusively expressed in neurons, but also in glial cells, suggesting a multicellular p...
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research
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Source: International Journal of Neuroscience - Category: Neuroscience Authors: Source Type: research
AbstractWith continuing cooperation from 18 domestic and international brain banks over the last 36  years, we have analyzed the aluminum content of the temporal lobe neocortex of 511 high-quality human female brain samples from 16 diverse neurological and neurodegenerative disorders, including 2 groups of age-matched controls. Temporal lobes (Brodmann areas A20–A22) were selected for analysis because of their availability and their central role in massive information-processing operations including efferent-signal integration, cognition, and memory formation. We used the analytical technique of (i) Zeeman-type ...
Source: Molecular Neurobiology - Category: Neurology Source Type: research
In this study, we show that calorie restriction is protective against age-related increases in senescence and microglia activation and pro-inflammatory cytokine expression in an animal model of aging. Further, these protective effects mitigated age-related decline in neuroblast and neuronal production, and enhanced olfactory memory performance, a behavioral index of neurogenesis in the SVZ. Our results support the concept that calorie restriction might be an effective anti-aging intervention in the context of healthy brain aging. Greater Modest Activity in Late Life Correlates with Lower Incidence of Dementia ...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Abstract Mutations in C9orf72 leading to hexanucleotide expansions are the most common genetic causes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A phenotype resembling ALS and FTD is seen in transgenic mice overexpressing the hexanucleotide expansions, but is absent in C9orf72-deficient mice. Thus, the exact function of C9orf72 in neurons and how loss of C9orf72 may contribute to neuronal dysfunction remains to be clearly defined. Here, we showed that primary hippocampal neurons cultured from c9orf72 knockout mice have reduced dendritic arborization and spine density. Quantitative p...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research
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
Abstract Differentiated tissue is particularly vulnerable to alterations in protein and organelle homeostasis. The essential protein VCP, mutated in hereditary inclusion body myopathy, amyotrophic lateral sclerosis and frontotemporal dementia, is critical for efficient clearance of misfolded proteins and damaged organelles in dividing cells, but its role in terminally differentiated tissue affected by disease mutations is less clear. To understand the relevance of VCP in differentiated tissue, we inactivated it in skeletal muscle of adult mice. Surprisingly, knockout muscle demonstrated a necrotic myopathy with in...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research
Abstract A microsatellite expansion mutation in C9orf72 is the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). The expansion mutation leads to C9orf72 loss of function, RNA foci formation, and generation of five species of non-AUG RAN translated dipeptide repeat proteins (DPRs), such as poly(GA), poly(GP), poly(GR), poly(PA), and poly(PR). Although one cell can contain more than type of DPRs, information about interplay between different DPR species is limited. Here we show that the combined expression of distinct C9orf72-derived dipeptide repeat species produces...
Source: International Journal of Biological Macromolecules - Category: Biochemistry Authors: Tags: Int J Biol Macromol Source Type: research
AbstractNatural antisense transcripts are common features of mammalian genes providing additional regulatory layers of gene expression. A comprehensive description of antisense transcription inloci associated to familial neurodegenerative diseases may identify key players in gene regulation and provide tools for manipulating gene expression. We take advantage of the FANTOM5 sequencing datasets that represent the largest collection to date of genome-wide promoter usage in almost 2000 human samples. Transcription start sites (TSSs) are mapped at high resolution by the use of a modified protocol of cap analysis of gene expres...
Source: Molecular Neurobiology - Category: Neurology Source Type: research
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