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Cellular traffic jam seen in ALS/FTD -- Supports drug strategy

(Emory Health Sciences) A cellular traffic jam appears to affect neurons in most forms of ALS (amyotrophic lateral sclerosis), Emory/Mayo researchers have shown. The findings suggest that a drug strategy aimed at easing the traffic jam may be generalizable to sporadic and at least some familial types of ALS and FTD (frontotemporal dementia).
Source: EurekAlert! - Medicine and Health - Category: International Medicine & Public Health Source Type: news

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Mutations in CHCHD2 and CHCHD10 were recently reported in a broad spectrum of neurodegenerative diseases, e.g. Parkinson ’s disease, amyotrophic lateral sclerosis, frontotemporal dementia or mitochondrial myopathy (MM). The aim of the study was to evaluate the prevalence of CHCHD2 and CHCHD10 mutations in Italian MM patients without mitochondrial DNA mutations. The coding regions of CHCHD2 and CHCHD10 were sequenced in 62 MM patients. None of the patients showed CHCHD2 mutations, whereas one sporadic MM patient carried a homozygous Pro96Thr substitution in CHCHD10.
Source: Neurobiology of Aging - Category: Neuroscience Authors: Source Type: research
Publication date: Available online 1 February 2018 Source:Cell Author(s): Qiang Guo, Carina Lehmer, Antonio Martínez-Sánchez, Till Rudack, Florian Beck, Hannelore Hartmann, Manuela Pérez-Berlanga, Frédéric Frottin, Mark S. Hipp, F. Ulrich Hartl, Dieter Edbauer, Wolfgang Baumeister, Rubén Fernández-Busnadiego Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative diseases. Here, we address the elusive link between these phenomena by employing cryo-electron tomography to dissect the molecular architecture of protein aggr...
Source: Cell - Category: Cytology Source Type: research
AbstractA GGGGCC hexanucleotide repeat expansion in theC9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Neurodegeneration may occur via transcription of the repeats into inherently toxic repetitive sense and antisense RNA species, or via repeat-associated non-ATG initiated translation (RANT) of sense and antisense RNA into toxic dipeptide repeat proteins. We have previously demonstrated that regular interspersion of repeat RNA with stop codons prevents RANT (RNA-only models), allowing us to study the role of repeat RNA in isolation. Here we have created novel RNA-o...
Source: Acta Neuropathologica - Category: Neurology Source Type: research
In conclusion, the present study demonstrated that TIGIT is a prominent negative immune regulator involved in immunosenescence. This novel finding is highly significant, as targeting TIGIT might be an effective strategy to improve the immune response and decrease age-related comorbidities. Delivery of Extracellular Vesicles as a Potential Basis for Therapies https://www.fightaging.org/archives/2018/01/delivery-of-extracellular-vesicles-as-a-potential-basis-for-therapies/ Here I'll point out a readable open access review paper on the potential use of extracellular vesicles as a basis for therapy: harveste...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Why do humans live so much longer than other, short lived species? The researchers here provide evidence to suggest that it is a matter of many small changes, with the specific area of investigation being the the cellular repair mechanisms of autophagy. A world in which differences in longevity between species are the summed contributions from countless small effects is one in which we should discount the possibility that comparative genetic studies - between long-lived and short-lived humans, or between humans and other species - can yield silver bullets, findings that can on their own offer the potential to dramatically ...
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs
In this study, we investigated the presence of the G4C2 repeat expansion in 463 Brazilian probands, of whom 404 had ALS/motor neuron disease (ALS/MND) and 67 FTD, and in 63 healthy controls in the southeastern region of Brazil. The highest frequencies of the C9orf72 mutation were in the ALS-FTD group (50% of familial and 17.6% of sporadic cases), although it was also present in 5% of pure ALS/MND patients (11.8% of familial and 3.6% of sporadic cases) and in 7.1% of pure familial FTD.
Source: Neurobiology of Aging - Category: Neuroscience Authors: Tags: Brief communication Source Type: research
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 &nda...
Source: Neurological Sciences - Category: Neurology Source Type: research
by Iris Broce, Celeste M. Karch, Natalie Wen, Chun C. Fan, Yunpeng Wang, Chin Hong Tan, Naomi Kouri, Owen A. Ross, G ünter U. Höglinger, Ulrich Muller, John Hardy, International FTD-Genomics Consortium , Parastoo Momeni, Christopher P. Hess, William P. Dillon, Zachary A. Miller, Luke W. Bonham, Gil D. Rabinovici, Howard J. Rosen, Gerard D. Schellenberg, Andre Franke, Tom H. Karlsen, Jan H. Veldink, Raffaele Ferr ari, Jennifer S. Yokoyama, Bruce L. Miller, Ole A. Andreassen, Anders M. Dale, Rahul S. Desikan, Leo P. Sugrue BackgroundConverging evidence suggests that immune-mediated dysfunction plays an important ro...
Source: PLoS Medicine - Category: Internal Medicine Authors: Source Type: research
Publication date: 2018 Source:Handbook of Clinical Neurology, Volume 147 Author(s): Henry Paulson More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy...
Source: Handbook of Clinical Neurology - Category: Neurology Source Type: research
AbstractThe exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion inC9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine –arginine and proline–arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these ...
Source: Acta Neuropathologica - Category: Neurology Source Type: research
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