FUS

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RNA-binding protein FUS (75 kDa DNA-pairing protein) (Oncogene FUS) (Oncogene TLS) (POMp75) (Translocated in liposarcoma protein) [TLS]

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Altered miRNA and mRNA Expression in Sika Deer Skeletal Muscle with Age.

Studies of the gene and miRNA expression profiles associated with the postnatal late growth, development, and aging of skeletal muscle are lacking in sika deer. To understand the molecular mechanisms of the growth and development of sika deer skeletal muscle, we used de novo RNA sequencing (RNA-seq) and microRNA sequencing (miRNA-seq) analyses to determine the differentially expressed (DE) unigenes and miRNAs from skeletal muscle tissues at 1, 3, 5, and 10 years in sika deer. A total of 51,716 unigenes, 171 known miRNAs, and 60 novel miRNAs were identified based on four mRNA and small RNA libraries. A total of 2,044 unigenes and 11 miRNAs were differentially expressed between adolescence and juvenile sika deer, 1,946 unigenes and 4 miRNAs were differentially expressed between adult and adolescent sika deer, and 2,209 unigenes and 1 miRNAs were differentially expressed between aged and adult sika deer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that DE unigenes and miRNA were mainly related to energy and substance metabolism, processes that are closely associate with the growth, development, and aging of skeletal muscle. We also constructed mRNA-mRNA and miRNA-mRNA interaction networks related to the growth, development, and aging of skeletal muscle. The results show that mRNA (Myh1, Myh2, Myh7, ACTN3, etc.) and miRNAs (miR-133a, miR-133c, miR-192, miR-151-3p, etc.) may play important roles in muscle growth and development, and mRNA (WWP1, DEK, UCP3, FUS, etc.) and miRNAs (miR-17-5p, miR-378b, miR-199a-5p, miR-7, etc.) may have key roles in muscle aging. In this study, we determined the dynamic miRNA and unigenes transcriptome in muscle tissue for the first time in sika deer. The age-dependent miRNAs and unigenes identified will offer insights into the molecular mechanism underlying muscle development, growth, and maintenance and will also provide valuable information for sika deer genetic breeding.

MeSH Terms

  • Aging
  • Animals
  • Deer
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • High-Throughput Nucleotide Sequencing
  • MicroRNAs
  • Muscle Development
  • Muscle, Skeletal
  • RNA, Messenger
  • Transcriptome

Keywords

  • age-dependent
  • mRNA
  • microRNA
  • sika deer
  • skeletal muscles


HPV shapes tumor transcriptome by globally modifying the pool of RNA binding protein-binding motif.

Human papillomavirus (HPV) positive head and neck cancer displayed specific transcription landscape but the underlying molecular mechanisms are not fully determined. Here, we interestingly found that HPV infection could globally elongate the 3'-untranslated regions (3'UTRs) in the majority of alternative polyadenylation (APA)-containing genes. Counterintuitively, the 3'UTR elongation does not affect their resident gene expression. Rather, they significantly increase the number of binding sites for RNA-binding proteins (RBPs) and subsequently upregulate a group of oncogenic genes by absorbing RBPs. A significant fraction of HPV affected genes are regulated through such mechanism that is 3'UTR-mediated recruitment of RBPs. As an example, we observed that HPV infection increases the length of 3'UTR of RBM25 transcript and hence recruits much more RNA binding protein including FUS and DGCR8. Consequently, in the absence of FUS and DGCR8 regulation, PD-1 was rescued and up-regulated after HPV infection. Taken together, our findings not only suggest a novel paradigm of how oncogenic viruses shape tumor transcriptome by modifying the 3'UTR, but also present a previously unrecognized layer of APA-RBP interplay in this molecular hierarchy. Modification of the pool of RBP-binding motif might expand our understandings into virus-associated carcinogenesis.

MeSH Terms

  • 3' Untranslated Regions
  • Databases, Genetic
  • Head and Neck Neoplasms
  • Humans
  • MicroRNAs
  • Papillomaviridae
  • Papillomavirus Infections
  • Squamous Cell Carcinoma of Head and Neck
  • Transcriptome
  • Up-Regulation

Keywords

  • PD-1
  • RBM25
  • RNA-binding protein
  • age-related disease
  • aging
  • alternative polyadenylation
  • oncogenic viruses


Memory Decline and Its Reversal in Aging and Neurodegeneration Involve miR-183/96/182 Biogenesis.

Aging is characterized by progressive memory decline that can lead to dementia when associated with neurodegeneration. Here, we show in mice that aging-related memory decline involves defective biogenesis of microRNAs (miRNAs), in particular miR-183/96/182 cluster, resulting from increased protein phosphatase 1 (PP1) and altered receptor SMAD (R-SMAD) signaling. Correction of the defect by miR-183/96/182 overexpression in hippocampus or by environmental enrichment that normalizes PP1 activity restores memory in aged animals. Regulation of miR-183/96/182 biogenesis is shown to involve the neurodegeneration-related RNA-binding proteins TDP-43 and FUS. Similar alterations in miR-183/96/182, PP1, and R-SMADs are observed in the brains of patients with amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases with pathological aggregation of TDP-43. Overall, these results identify new mechanistic links between miR-183/96/182, PP1, TDP-43, and FUS in age-related memory deficits and their reversal.

MeSH Terms

  • Aging
  • Amyotrophic Lateral Sclerosis
  • Animals
  • Cell Line, Tumor
  • Cell Nucleus
  • Cognition Disorders
  • Frontotemporal Lobar Degeneration
  • Hippocampus
  • Humans
  • Memory Disorders
  • Mice, Inbred C57BL
  • MicroRNAs
  • Nerve Degeneration
  • Protein Phosphatase 1
  • RNA-Binding Protein FUS
  • Smad Proteins

Keywords

  • Dementia
  • FUS
  • Memory
  • Protein phosphatase 1
  • TDP-43
  • microRNA


[Development of imaging-based diagnostic procedures for brain protein aging using a mouse model of tauopathy].

An increasing age is the greatest risk factor for dementia and related disorders. Therefore, much attention has been focus on researches to understand mechanisms of disease-related brain aging. Neurodegenerative diseases including Alzheimer's disease (AD), dementia with lewy bodies, and frontotemporal lobar degeneration are mostly diagnosed by neuropathological features with protein inclusions such as Aβ, tau, α-synuclein, TDP-43, and FUS. These proteins are expected to lose physiological functions and mutual interaction with functional molecule with aging. Consecutively, acquired pathogenicities of aged proteins are accumulated and propagated in neural cells. The research for "Brain protein aging" is developed for understanding the mechanisms of initiation and pathogenicity of aging. Tau protein is one of major components of neurofibrillary tangles, which are closely associated with the severity of brain function loss of AD. To investigate tau protein's Brain protein aging, we have currently developed the in vivo multimodal imaging techniques for visualizing the progression of tau pathology. In this review, we will introduce such a novel imaging-based diagnostic procedures on a mouse model of tauopathy.

MeSH Terms

  • Aging
  • Animals
  • Brain
  • Disease Models, Animal
  • Mice
  • Multimodal Imaging
  • Tauopathies
  • alpha-Synuclein
  • tau Proteins


Riluzole does not improve lifespan or motor function in three ALS mouse models.

Riluzole is the most widespread therapeutic for treatment of the progressive degenerative disease amyotrophic lateral sclerosis (ALS). Riluzole gained FDA approval in 1995 before the development of ALS mouse models. We assessed riluzole in three transgenic ALS mouse models: the SOD1 model, the TDP-43 model, and the recently developed FUS (1-359) model. Age, sex and litter-matched mice were treated with riluzole (22 mg/kg) in drinking water or vehicle (DMSO) from symptom onset. Lifespan was assessed and motor function tests were carried out twice weekly to determine whether riluzole slowed disease progression. Riluzole treatment had no significant benefit on lifespan in any of the ALS mouse models tested. Riluzole had no significant impact on decline in motor performance in the FUS (1-359) and SOD1 transgenic mice as assessed by Rotarod and stride length analysis. Riluzole is widely prescribed for ALS patients despite questions surrounding its efficacy. Our data suggest that if riluzole was identified as a therapeutic candidate today it would not progress past pre-clinical assessment. This raises questions about the standards used in pre-clinical assessment of therapeutic candidates for the treatment of ALS.

MeSH Terms

  • Amyotrophic Lateral Sclerosis
  • Animals
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Disease Progression
  • Kaplan-Meier Estimate
  • Longevity
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuroprotective Agents
  • RNA-Binding Protein FUS
  • Riluzole
  • Superoxide Dismutase

Keywords

  • ALS
  • Riluzole
  • SOD1
  • transgenic animals


Investigation of the Safety of Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Natural Canine Model of Aging.

Ultrasound-mediated opening of the Blood-Brain Barrier(BBB) has shown exciting potential for the treatment of Alzheimer's disease(AD). Studies in transgenic mouse models have shown that this approach can reduce plaque pathology and improve spatial memory. Before clinical translation can occur the safety of the method needs to be tested in a larger brain that allows lower frequencies be used to treat larger tissue volumes, simulating clinical situations. Here we investigate the safety of opening the BBB in half of the brain in a large aged animal model with naturally occurring amyloid deposits. Aged dogs naturally accumulate plaques and show associated cognitive declines. Low-frequency ultrasound was used to open the BBB unilaterally in aged beagles (9-11yrs, n=10) in accordance with institutionally approved protocols. Animals received either a single treatment or four weekly treatments. Magnetic resonance imaging(MRI) was used to guide the treatments and assess the tissue effects. The animals underwent neurological testing during treatment follow-up, and a follow-up MRI exam 1 week following the final treatment. The permeability of the BBB was successfully increased in all animals (mean enhancement: 19±11% relative to untreated hemisphere). There was a single adverse event in the chronic treatment group that resolved within 24 hrs. Follow-up MRI showed the BBB to be intact with no evidence of tissue damage in all animals. Histological analysis showed comparable levels of microhemorrhage between the treated and control hemispheres in the prefrontal cortex (single/repeat treatment: 1.0±1.4 vs 0.4±0.5/5.2±1.8 vs. 4.0±2.0). No significant differences were observed in beta-amyloid load (single/repeat: p=0.31/p=0.98) although 3/5 animals in each group showed lower Aβ loads in the treated hemisphere. Whole-hemisphere opening of the BBB was well tolerated in the aged large animal brain. The treatment volumes and frequencies used are clinically relevant and indicate safety for clinical translation. Further study is warranted to determine if FUS has positive effects on naturally occurring amyloid pathology.

MeSH Terms

  • Aging
  • Animals
  • Blood-Brain Barrier
  • Capillary Permeability
  • Dogs
  • Plaque, Amyloid
  • Ultrasonic Therapy

Keywords

  • Alzheimer's Disease
  • Blood-Brain Barrier
  • Focused Ultrasound


Glutamate release and uptake processes are altered in a new mouse model of amyotrophic lateral sclerosis.

In this paper, we showed that in the cortex of mice expressing an abberant form of FUS protein that model amyotrophic lateral sclerosis (ALS), the processes of KCl-induced and basal [(3)H]glutamate release and uptake are altered at the presymptomatic stage as compared to the non-transgenic littermates. The change in these three parameters in transgenic animals causes excitotoxicity, which, in turn, may lead to massive loss of motor neurons and the onset of ALS symptoms.

MeSH Terms

  • Aging
  • Amyotrophic Lateral Sclerosis
  • Animals
  • Cations, Monovalent
  • Central Nervous System Agents
  • Cerebral Cortex
  • Disease Models, Animal
  • Glutamic Acid
  • Mice, Transgenic
  • Potassium
  • Potassium Chloride
  • RNA-Binding Protein FUS
  • Sodium
  • Synaptosomes
  • Tritium


FUS-linked essential tremor associated with motor dysfunction in Drosophila.

Essential tremor (ET) is one of the most common adult-onset neurological disorders which produce motor and non-motor symptoms. To date, there are no gold standard pathological hallmarks of ET, and despite a strong genetic contribution toward ET development, only a few pathogenic mutations have been identified. Recently, a pathogenic FUS-Q290X mutation has been reported in a large ET-affected family; however, the pathophysiologic mechanism underlying FUS-linked ET is unknown. Here, we generated transgenic Drosophila expressing hFUS-WT and hFUS-Q290X and targeted their expression in different tissues. We found that the targeted expression of hFUS-Q290X in the dopaminergic and the serotonergic neurons did not cause obvious neuronal degeneration, but it resulted in motor dysfunction which was accompanied by impairment in the GABAergic pathway. The involvement of the GABAergic pathway was supported by rescue of motor symptoms with gabapentin. Interestingly, we observed gender specific downregulation of GABA-R and NMDA-R expression and reduction in serotonin level. Overexpression of hFUS-Q290X also caused an increase in longevity and this was accompanied by downregulation of the IIS/TOR signalling pathway. Our in vivo studies of the hFUS-Q290X mutation in Drosophila link motor dysfunction to impairment in the GABAergic pathway. Our findings would facilitate further efforts in unravelling the pathophysiology of ET.

MeSH Terms

  • Amines
  • Animals
  • Animals, Genetically Modified
  • Cyclohexanecarboxylic Acids
  • Disease Models, Animal
  • Dopaminergic Neurons
  • Drosophila melanogaster
  • Essential Tremor
  • GABAergic Neurons
  • Gabapentin
  • Gene Expression Regulation, Developmental
  • Humans
  • Longevity
  • Motor Disorders
  • Mutation
  • Organ Specificity
  • RNA-Binding Protein FUS
  • Receptors, GABA
  • Receptors, N-Methyl-D-Aspartate
  • Serotonergic Neurons
  • gamma-Aminobutyric Acid


FET proteins regulate lifespan and neuronal integrity.

The FET protein family includes FUS, EWS and TAF15 proteins, all of which have been linked to amyotrophic lateral sclerosis, a fatal neurodegenerative disease affecting motor neurons. Here, we show that a reduction of FET proteins in the nematode Caenorhabditis elegans causes synaptic dysfunction accompanied by impaired motor phenotypes. FET proteins are also involved in the regulation of lifespan and stress resistance, acting partially through the insulin/IGF-signalling pathway. We propose that FET proteins are involved in the maintenance of lifespan, cellular stress resistance and neuronal integrity.

MeSH Terms

  • Animals
  • Astemizole
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Insulin
  • Longevity
  • Mutation
  • Neurons
  • Signal Transduction
  • Somatomedins
  • Stress, Physiological


ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function.

The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.

MeSH Terms

  • Amyotrophic Lateral Sclerosis
  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Cytoplasmic Granules
  • Disease Models, Animal
  • Frontotemporal Lobar Degeneration
  • Hydrogels
  • Longevity
  • Motor Activity
  • Mutation
  • Phase Transition
  • RNA, Messenger
  • RNA-Binding Protein FUS
  • Ribonucleoproteins


A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation.

Many proteins contain disordered regions of low-sequence complexity, which cause aging-associated diseases because they are prone to aggregate. Here, we study FUS, a prion-like protein containing intrinsically disordered domains associated with the neurodegenerative disease ALS. We show that, in cells, FUS forms liquid compartments at sites of DNA damage and in the cytoplasm upon stress. We confirm this by reconstituting liquid FUS compartments in vitro. Using an in vitro "aging" experiment, we demonstrate that liquid droplets of FUS protein convert with time from a liquid to an aggregated state, and this conversion is accelerated by patient-derived mutations. We conclude that the physiological role of FUS requires forming dynamic liquid-like compartments. We propose that liquid-like compartments carry the trade-off between functionality and risk of aggregation and that aberrant phase transitions within liquid-like compartments lie at the heart of ALS and, presumably, other age-related diseases.

MeSH Terms

  • Aging
  • Amyotrophic Lateral Sclerosis
  • Cell Nucleus
  • Cytoplasm
  • Humans
  • Mutation
  • Prions
  • Protein Aggregates
  • Protein Structure, Tertiary
  • RNA-Binding Protein FUS


Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons.

Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron disease with no current effective treatment. Accumulation of abnormal protein inclusions containing SOD1, TARDBP, FUS, among other proteins, is a pathological hallmark of ALS. Autophagy is the major degradation pathway involved in the clearance of damaged organelles and protein aggregates. Although autophagy has been shown to efficiently degrade ALS-linked mutant protein in cell culture models, several studies suggest that autophagy impairment may also contribute to disease pathogenesis. In this report, we tested the potential use of trehalose, a disaccharide that induces MTOR-independent autophagy, in the development of experimental ALS. Administration of trehalose to mutant SOD1 transgenic mice significantly prolonged life span and attenuated the progression of disease signs. These effects were associated with decreased accumulation of SOD1 aggregates and enhanced motoneuron survival. The protective effects of trehalose were associated with increased autophagy levels in motoneurons. Cell culture experiments demonstrated that trehalose led to mutant SOD1 degradation by autophagy in NSC34 motoneuron cells and also protected primary motoneurons against the toxicity of conditioned media from mutant SOD1 transgenic astrocytes. At the mechanistic level, trehalose treatment led to a significant upregulation in the expression of key autophagy-related genes at the mRNA level including Lc3, Becn1, Sqstm1 and Atg5. Consistent with these changes, trehalose administration enhanced the nuclear translocation of FOXO1, an important transcription factor involved in the activation of autophagy in neurons. This study suggests a potential use of trehalose and enhancers of MTOR-independent autophagy for the treatment of ALS.

MeSH Terms

  • Amyotrophic Lateral Sclerosis
  • Animals
  • Autophagy
  • Cell Survival
  • Cytoprotection
  • Disease Progression
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Humans
  • Longevity
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Neurons
  • Mutation
  • Neuroglia
  • Protein Structure, Quaternary
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord
  • Superoxide Dismutase
  • Transcription, Genetic
  • Trehalose

Keywords

  • amyotrophic lateral sclerosis
  • autophagy
  • copper-zinc superoxide dismutase 1
  • protein aggregation
  • trehalose