ALS, rare dementia share genetic link

(Washington University School of Medicine) Studying data from more than 125,000 individuals, an international team of researchers led by scientists at Washington University School of Medicine in St. Louis has identified genetic links between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The link between the seemingly unrelated disorders suggests that some drugs developed to treat ALS also may work against frontotemporal dementia and vice versa.
Source: EurekAlert! - Social and Behavioral Science - Category: International Medicine & Public Health Source Type: news

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Authors: Kiousi V, Arnaoutoglou M, Printza A Abstract Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease that belongs to the group of motor neuron diseases. Motor deficits like reduce in tongue strength, may coexist with cognitive deficits compatible with frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD). FTD is a neurodegenerative syndrome with two main clinical variants: behavioral (bvFTD) and language or Primary Progressive Aphasia (PPA). ALS and FTD have significant clinical and neuropathological overlapping so that for some researchers they are ...
Source: Hellenic Journal of Nuclear Medicine - Category: Nuclear Medicine Tags: Hell J Nucl Med Source Type: research
Conclusion: This is the first study cohort identifying the underlyingC9ORF72 expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum. Analysis of theC9ORF72 expansion should be considered for patients with probable iNPH presenting with frontal atrophy and personality changes or other severe psychiatric symptoms.Dement Geriatr Cogn Disord 2019;47:91 –103
Source: Dementia and Geriatric Cognitive Disorders - Category: Geriatrics Source Type: research
We reported patients, carrying the p.Ser59Leu heterozygous mutation inCHCHD10, from a large family with a mitochondrial myopathy associated with motor neuron disease (MND). Rapidly, our group and others reportedCHCHD10 mutations in amyotrophic lateral sclerosis (ALS), frontotemporal dementia-ALS and other neurodegenerative diseases. Here, we generated knock-in (KI) mice, carrying the p.Ser59Leu mutation, that mimic the mitochondrial myopathy with mtDNA instability displayed by the patients from our original family. Before 14  months of age, all KI mice developed a fatal mitochondrial cardiomyopathy associated with enh...
Source: Acta Neuropathologica - Category: Neurology Source Type: research
CONCLUSION: This is the first study cohort identifying the underlying C9ORF72 expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum. Analysis of the C9ORF72 expansion should be considered for patients with probable iNPH presenting with frontal atrophy and personality changes or other severe psychiatric symptoms. PMID: 30861516 [PubMed - as supplied by publisher]
Source: Dementia and Geriatric Cognitive Disorders - Category: Psychiatry Tags: Dement Geriatr Cogn Disord Source Type: research
AbstractThe commonest genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a large hexanucleotide expansion within the non-coding region of theC9orf72 gene. The pathogenic mechanisms of the mutation seem toxic gain of functions, while haploinsufficiency alone appears insufficient to cause neurodegeneration.C9orf72−/− mice rather develop features of autoimmunity. Immune-mediated dysfunctions are involved in the pathogenesis of ALS and FTD and high prevalence of autoimmune disease has recently been observed inC9orf72 expansion-positive patients. Since intermediate repeat expan...
Source: NeuroMolecular Medicine - Category: Neurology Source Type: research
Modelling of neurological diseases can be done in mono ‐cultures for many readouts, but for authentic modelling of neuron‐microglia interactions such as synapse pruning events it is crucial to use co‐cultures. AbstractInflammation of the brain and the consequential immunological responses play pivotal roles in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia (FTD). Microglia, the resident macrophage cells of the brain, have also emerged as key players in neuroinflammation. As primary human microglia from living subjects are normall...
Source: Stem Cells - Category: Stem Cells Authors: Tags: Embryonic Stem Cells/Induced Pluripotent Stem Cells Source Type: research
Publication date: Available online 7 March 2019Source: NeuronAuthor(s): Fatima Gasset-Rosa, Shan Lu, Haiyang Yu, Cong Chen, Ze’ev Melamed, Lin Guo, James Shorter, Sandrine Da Cruz, Don W. ClevelandSummaryWhile cytoplasmic aggregation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia, how aggregates form and what drives its nuclear clearance have not been determined. Here we show that TDP-43 at its endogenous level undergoes liquid-liquid phase separation (LLPS) within nuclei in multiple cell types. Increased concentration of TDP-43 in the cytoplasm or transient exposure...
Source: Neuron - Category: Neuroscience Source Type: research
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Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
We present an optogenetic approach to reliably induce TDP-43 proteinopathy under spatiotemporal control. We show that the formation of pathologically relevant inclusions is driven by aberrant interactions between low-complexity domains of TDP-43 that are antagonized by RNA binding. Although stress granules are hypothesized to be a conduit for seeding TDP-43 proteinopathy, we demonstrate pathological inclusions outside these RNA-rich structures. Furthermore, we show that aberrant phase transitions of cytoplasmic TDP-43 are neurotoxic and that treatment with oligonucleotides composed of TDP-43 target sequences prevent inclus...
Source: Neuron - Category: Neuroscience Source Type: research
The cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of degenerating neurons in amyotrophic lateral sclerosis (ALS) and subsets of frontotemporal dementia (FTD). In order to reduce TDP-43 pathology, we generated single-chain (scFv) antibodies against the RNA recognition motif 1 (RRM1) of TDP-43, which is involved in abnormal protein self-aggregation and interaction with p65 NF-κB. Virus-mediated delivery into the nervous system of a scFv antibody, named VH7Vk9, reduced microgliosis in a mouse model of acute neuroinflammation and mitigated cognitive impairment, motor defects, TDP-43 protein...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
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