Synaptic Paths to Neurodegeneration: The Emerging Role of TDP-43 and FUS in Synaptic Functions.

Synaptic Paths to Neurodegeneration: The Emerging Role of TDP-43 and FUS in Synaptic Functions. Neural Plast. 2018;2018:8413496 Authors: Ling SC Abstract TAR DNA-binding protein-43 KDa (TDP-43) and fused in sarcoma (FUS) as the defining pathological hallmarks for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coupled with ALS-FTD-causing mutations in both genes, indicate that their dysfunctions damage the motor system and cognition. On the molecular level, TDP-43 and FUS participate in the biogenesis and metabolism of coding and noncoding RNAs as well as in the transport and translation of mRNAs as part of cytoplasmic mRNA-ribonucleoprotein (mRNP) granules. Intriguingly, many of the RNA targets of TDP-43 and FUS are involved in synaptic transmission and plasticity, indicating that synaptic dysfunction could be an early event contributing to motor and cognitive deficits in ALS and FTD. Furthermore, the ability of the low-complexity prion-like domains of TDP-43 and FUS to form liquid droplets suggests a potential mechanism for mRNP assembly and conversion. This review will discuss the role of TDP-43 and FUS in RNA metabolism, with an emphasis on the involvement of this process in synaptic function and neuroprotection. This will be followed by a discussion of the potential phase separation mechanism for forming RNP granules and pathological inclusions. PMID: 29755516 [PubMed - in process]
Source: Neural Plasticity - Category: Neurology Authors: Tags: Neural Plast Source Type: research

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Publication date: Available online 24 November 2018Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Junghee Lee, Phuong T. Nguyen, Hyun-Soo Shim, Seung Jae Hyeon, Hyeonjoo Im, Mi-Hyun Choi, Sooyoung Chung, Neil W. Kowall, Sean Bong Lee, Hoon RyuAbstractEwing's sarcoma (EWS) is a bone cancer arising predominantly in young children. EWSR1 (Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1) gene is ubiquitously expressed in most cell types, indicating it has diverse roles in various cellular processes and organ development. Recently, several studies have shown that missense mutation...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research
Publication date: 24 July 2018Source: Cell Reports, Volume 24, Issue 4Author(s): Eva-Maria Hock, Zuzanna Maniecka, Marian Hruska-Plochan, Stefan Reber, Florent Laferrière, Sonu Sahadevan M.K., Helena Ederle, Lauren Gittings, Lucas Pelkmans, Luc Dupuis, Tammaryn Lashley, Marc-David Ruepp, Dorothee Dormann, Magdalini PolymenidouSummaryThe primarily nuclear RNA-binding protein FUS (fused in sarcoma) forms pathological cytoplasmic inclusions in a subset of early-onset amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. In response to cellular stress, FUS is recruited to cytoplasmic stress gra...
Source: Cell Reports - Category: Cytology Source Type: research
Abnormal intracellular accumulation of the fused in sarcoma (FUS) protein is the characteristic pathological feature of cases of familial amyotrophic lateral sclerosis (ALS) caused by FUS mutations (ALS-FUS) and several uncommon disorders that may present with sporadic frontotemporal dementia (FTLD-FUS). Although these findings provide further support for the concept that ALS and FTD are closely related clinical syndromes with an overlapping molecular basis, important differences in the pathological features and results from experimental models indicate that ALS-FUS and FTLD-FUS have distinct pathogenic mechanisms.
Source: Cold Spring Harbor perspectives in medicine - Category: Research Authors: Tags: Prion Diseases PERSPECTIVES Source Type: research
Abstract Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid-liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with...
Source: The Biochemical Journal - Category: Biochemistry Authors: Tags: Biochem J Source Type: research
Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid–liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, incl...
Source: Biochemical Journal - Category: Biochemistry Authors: Tags: Review Articles Source Type: research
This article is protected by copyright. All rights reserved.
Source: FEBS Letters - Category: Biochemistry Authors: Tags: Review Source Type: research
Publication date: October 2016 Source:Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1862, Issue 10 Author(s): Marisa Kamelgarn, Jing Chen, Lisha Kuang, Alexandra Arenas, Jianjun Zhai, Haining Zhu, Jozsef Gal Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Mutations in the Fused in Sarcoma/Translocated in Liposarcoma (FUS/TLS) gene cause a subset of familial ALS cases and are also implicated in sporadic ALS. FUS is typically localized to the nucleus. The ALS-related FUS mutations cause cytoplasmic mis-localization and the formation of stress granule-like structures...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research
This article is part of the Frontotemporal Dementia special issue. The two major RNA Binding Proteins involved in Amyotrophic Lateral Sclerosisi and Frontotemporal Dementia are TDP‐43 and FUST/TLS. Both proteins are involved in regulating all aspects of RNA and RNA life cycle within neurons, from transcription, processing, and transport/stability to the formation of cytoplasmic and nuclear stress granules. For this reason, the aberrant aggregation of these factors during disease can impair multiple RNA metabolic pathways and eventually lead to neuronal death/inactivation. The purpose of this review is to provide an up...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: Review Source Type: research
This article is protected by copyright. All rights reserved.
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: Review Source Type: research
Conclusions: This study revealed a characteristic phenotype in FUS/TLS‐linked FALS patients in Japan. FUS/TLS screening is recommended in patients with FALS with this phenotype. Muscle Nerve, 2016
Source: Muscle and Nerve - Category: Internal Medicine Authors: Tags: Research Article Source Type: research
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