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1.
Nat Commun ; 12(1): 513, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479240

RESUMO

Missense mutations in Valosin-Containing Protein (VCP) are linked to diverse degenerative diseases including IBMPFD, amyotrophic lateral sclerosis (ALS), muscular dystrophy and Parkinson's disease. Here, we characterize a VCP-binding co-factor (SVIP) that specifically recruits VCP to lysosomes. SVIP is essential for lysosomal dynamic stability and autophagosomal-lysosomal fusion. SVIP mutations cause muscle wasting and neuromuscular degeneration while muscle-specific SVIP over-expression increases lysosomal abundance and is sufficient to extend lifespan in a context, stress-dependent manner. We also establish multiple links between SVIP and VCP-dependent disease in our Drosophila model system. A biochemical screen identifies a disease-causing VCP mutation that prevents SVIP binding. Conversely, over-expression of an SVIP mutation that prevents VCP binding is deleterious. Finally, we identify a human SVIP mutation and confirm the pathogenicity of this mutation in our Drosophila model. We propose a model for VCP disease based on the differential, co-factor-dependent recruitment of VCP to intracellular organelles.


Assuntos
Longevidade/genética , Lisossomos/metabolismo , Proteínas de Membrana/genética , Mutação , Doenças Neurodegenerativas/genética , Proteínas de Ligação a Fosfato/genética , Proteína com Valosina/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/metabolismo , Doenças Neurodegenerativas/metabolismo , Osteíte Deformante/genética , Osteíte Deformante/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Ligação Proteica , Proteína com Valosina/metabolismo
2.
Adv Exp Med Biol ; 1281: 1-15, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433865

RESUMO

Frontotemporal dementia (FTD), particularly the behavioural variant (bvFTD) form, has fascinated researchers. Recent years have seen an increasing interest in aspects of bvFTD that extend beyond the initial focus on cognitive changes and frontal executive dysfunction. Changes have been identified in aspects including fundamental changes in physiology and metabolism, and cognitive domains such as episodic memory. Work on social cognition has emphasised the importance of a breakdown in interpreting and expressing emotions, while the overlap between psychiatric disorders and bvFTD has been brought into focus by the finding of high rates of psychotic features in carriers of the c9orf72 gene expansion. We review these aspects in the chapter " Behavioural variant frontotemporal dementia: Recent advances in diagnosis and understanding of the disorder" and also potential markers of disease progression and early diagnosis that may aid in the development of treatment options, which have thus far eluded us.


Assuntos
Demência Frontotemporal , Biomarcadores , Proteína C9orf72 , Diagnóstico Diferencial , Progressão da Doença , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Humanos , Testes Neuropsicológicos
3.
Adv Exp Med Biol ; 1281: 67-76, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433869

RESUMO

The identification of C9orf72 gene has led to important scientific progresses and has considerably changed our clinical practice. However, a decade after C9orf72 discovery, some important clinical questions remain unsolved. The reliable cutoff for the pathogenic repeat number and the implication of intermediate alleles in frontotemporal dementia, amyotrophic lateral sclerosis, or in other diseases are still uncertain. The occurrence of an anticipation phenomenon - at the clinical and molecular levels - in C9orf72 kindreds is still debated as well, and the factors driving age at onset and phenotype variability are largely unknown. All these questions have a significant impact not only in clinical practice for diagnosis and genetic counseling but also in a research context for the initiation of therapeutic trials. In this chapter, we will address all those issues and summarize the recent updates about clinical aspects of C9orf72 disease, focusing on both the common and the less typical phenotypes.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Doença de Pick , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Expansão das Repetições de DNA/genética , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Humanos , Proteínas/genética
4.
Adv Exp Med Biol ; 1281: 113-121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433872

RESUMO

Around one-third of frontotemporal dementia (FTD) is autosomal dominant with the major genetic causes being mutations in MAPT, GRN and C9orf72. Studying familial forms of FTD can provide a window into the earliest stages of the illness, many years before symptoms start. Large cohort studies have been set up in recent years to better understand this presymptomatic phase, including the Genetic FTD Initiative (GENFI) and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (ARTFL/LEFFTDS) studies. Whilst these studies have focused on the investigation of a variety of aspects of genetic FTD, from understanding the molecular pathogenesis to developing biomarkers, they also have a common goal: finding a way to prevent FTD. Researchers from these cohort studies have therefore come together to form the FTD Prevention Initiative (FPI), which has the overarching aim of promoting clinical trials of new therapies to prevent FTD through creating an international database of participants eligible for trials and uniform standards for conducting such trials. This chapter outlines the work of the FPI so far and its future goals over the next few years.


Assuntos
Demência Frontotemporal , Doença de Pick , Proteína C9orf72/genética , Estudos de Coortes , Demência Frontotemporal/genética , Demência Frontotemporal/prevenção & controle , Humanos , Mutação , Proteínas tau/genética
5.
Adv Exp Med Biol ; 1281: 141-150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433874

RESUMO

It is predictable that syndromes of frontotemporal dementia (FTD) may have a worldwide distribution; however, data available on their incidence and prevalence are variable. This variability most likely reflects disparities across regions in the distribution of the expertise, technology, and resources available for FTD research and care. Important discoveries have been made regarding FTD's phenotypes, genetics, and cultural influences on the expression of symptoms; however, in many countries, there are barriers posed by a dearth of resources. There are pressing needs to further develop research on FTD: including first, population studies designed to fill the gaps in our knowledge about FTD's frequency and risk factors in developing regions and among minority groups in developed countries. It is also necessary to facilitate the psychometric characterization of contemporary diagnostic criteria and their translation to different languages and cultural contexts. Furthermore, much needed is the analysis of differences in the genetic risk factors for FTD, particularly non-Mendelian susceptibility factors. It is hoped that reflections on FTD from an international perspective will spur an extension of the vibrant multicenter collaborations, that exist in North America and Europe, toward new centers to be established and supported in the developing regions of the world.


Assuntos
Demência Frontotemporal , Doença de Pick , Comparação Transcultural , Europa (Continente) , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/epidemiologia , Demência Frontotemporal/genética , Humanos , América do Norte
6.
Adv Exp Med Biol ; 1281: 123-139, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433873

RESUMO

A timely diagnosis of frontotemporal degeneration (FTD) is frequently challenging due to the heterogeneous symptomatology and poor phenotype-pathological correlation. Fluid biomarkers that reflect FTD pathophysiology could be instrumental in both clinical practice and pharmaceutical trials. In recent years, significant progress has been made in developing biomarkers of neurodegenerative diseases: amyloid-ß and tau in cerebrospinal fluid (CSF) can be used to exclude Alzheimer's disease, while neurofilament light chain (NfL) is emerging as a promising, albeit nonspecific, marker of neurodegeneration in both CSF and blood. Gene-specific biomarkers such as PGRN in GRN mutation carriers and dipeptide repeat proteins in C9orf72 mutation carriers are potential target engagement markers in genetic FTD trials. Novel techniques capable of measuring very low concentrations of brain-derived proteins in peripheral fluids are facilitating studies of blood biomarkers as a minimally invasive alternative to CSF. A major remaining challenge is the identification of a biomarker that can be used to predict the neuropathological substrate in sporadic FTD patients.


Assuntos
Doença de Alzheimer , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Peptídeos beta-Amiloides , Biomarcadores , Proteína C9orf72 , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/genética , Humanos , Proteínas de Neurofilamentos , Proteínas tau/genética
7.
Adv Exp Med Biol ; 1281: 177-199, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433876

RESUMO

Filamentous inclusions of tau protein are found in cases of inherited and sporadic frontotemporal dementias (FTDs). Mutations in MAPT, the tau gene, cause approximately 5% of cases of FTD. They proved that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. Clinically and pathologically, cases with MAPT mutations can resemble sporadic diseases, such as Pick's disease, globular glial tauopathy, progressive supranuclear palsy and corticobasal degeneration. The structures of tau filaments from Pick's disease and corticobasal degeneration, determined by electron cryo-microscopy, revealed the presence of specific tau folds in each disease, with no inter-individual variation. The same was true of chronic traumatic encephalopathy.


Assuntos
Doença de Alzheimer , Demência Frontotemporal , Doença de Pick , Tauopatias , Demência Frontotemporal/genética , Humanos , Tauopatias/genética , Proteínas tau/genética
8.
Adv Exp Med Biol ; 1281: 269-282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433880

RESUMO

Frontotemporal dementia (FTD) is a neurodegenerative disease with high heritability. Almost half of all familial cases are caused by mutations in one of the three genes MAPT, GRN and C9orf72. Even though major advances in FTD research have been achieved during the last decades, it is not yet fully understood how mutations in these diverse genes lead to the disease. To improve our understanding of FTD, the Risk and Modifying Factors in Frontotemporal Dementia (RiMod-FTD) consortium has created an FTD-specific multi-omics data resource. Using multiple omics technologies on post-mortem brain tissue from patients with mutations in GRN, MAPT or C9orf72 and healthy controls, the resource aims to provide a comprehensive cellular profile of FTD. Furthermore, brain tissue from multiple mouse models and induced pluripotent stem cells (iPSC)-derived neuronal cultures were profiled with similar multi-omics technologies to make up for the shortcomings of post-mortem brain tissue. All data are publicly available to all researchers, and ongoing efforts aim to increase the available datasets and to improve their accessibility. The RiMod-FTD resource represents a uniquely valuable dataset for the field of FTD research, which we hope will accelerate the scientific progress in the field.


Assuntos
Demência Frontotemporal , Doenças Neurodegenerativas , Doença de Pick , Animais , Proteína C9orf72/genética , Demência Frontotemporal/genética , Humanos , Camundongos , Mutação , Proteínas tau/genética
9.
Adv Exp Med Biol ; 1281: 283-296, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433881

RESUMO

Frontotemporal dementia (FTD) is regarded as the second most common form of young-onset dementia after Alzheimer's disease (AD).FTD is a complex neurodegenerative condition characterised by heterogeneous clinical, pathological and genetic features. No efficient measures for early diagnosis and therapy are available.Familial (Mendelian) forms of disease have been studied over the past 20 years. Conversely, the genetics of sporadic forms of FTD (up to 70% of all cases) is understudied and still poorly understood. All this taken together suggests that more powerful and in-depth studies to tackle missing heritability and define the genetic architecture of sporadic FTD, with particular focus on the different subtypes (i.e. clinical and pathological diagnoses), are warranted.In parallel, it will be critical to translate the genetic findings into functional understanding of disease, i.e. moving from the identification of risk genes to the definition of risk pathways. It will be necessary to implement a paradigm shift - from reductionist to holistic approaches - to better interpret genetics and assist functional studies aimed at modelling and validating such risk pathways.In this chapter, we focus on the heterogeneous features of FTD touching upon its complex genetic landscape and discuss how novel approaches (e.g. computationally driven systems biology) promise to revolutionise the translation of genetic information into functional understanding of disease pathogenesis.


Assuntos
Doença de Alzheimer , Demência Frontotemporal , Doença de Pick , Simulação por Computador , Demência Frontotemporal/genética , Humanos
10.
Adv Exp Med Biol ; 1281: 243-267, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433879

RESUMO

Following the discovery of TDP-43 and FUS involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD), the major challenge in the field has been to understand their physiological functions, both in normal and disease conditions. The hope is that this knowledge will improve our understanding of disease and lead to the development of effective therapeutic options. Initially, the focus has been directed at characterizing the role of these proteins in the control of RNA metabolism, because the main function of TDP-43 and FUS is to bind coding and noncoding RNAs to regulate their life cycle within cells. As a result, we now have an in-depth picture of the alterations that occur in RNA metabolism following their aggregation in various ALS/FTLD models and, to a somewhat lesser extent, in patients' brains. In parallel, progress has been made with regard to understanding how aggregation of these proteins occurs in neurons, how it can spread in different brain regions, and how these changes affect various metabolic cellular pathways to result in neuronal death. The aim of this chapter will be to provide a general overview of the trending topics in TDP-43 and FUS investigations and to highlight what might represent the most promising avenues of research in the years to come.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Esclerose Amiotrófica Lateral/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Demência Frontotemporal/genética , Degeneração Lobar Frontotemporal/genética , Humanos , Proteína FUS de Ligação a RNA/genética
11.
PLoS Biol ; 18(12): e3001002, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33362237

RESUMO

Nucleocytoplasmic transport (NCT) defects have been implicated in neurodegenerative diseases such as C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, we identify a neuroprotective pathway of like-Sm protein 12 (LSM12) and exchange protein directly activated by cyclic AMP 1 (EPAC1) that sustains the nucleocytoplasmic RAN gradient and thereby suppresses NCT dysfunction by the C9ORF72-derived poly(glycine-arginine) protein. LSM12 depletion in human neuroblastoma cells aggravated poly(GR)-induced impairment of NCT and nuclear integrity while promoting the nuclear accumulation of poly(GR) granules. In fact, LSM12 posttranscriptionally up-regulated EPAC1 expression, whereas EPAC1 overexpression rescued the RAN gradient and NCT defects in LSM12-deleted cells. C9-ALS patient-derived neurons differentiated from induced pluripotent stem cells (C9-ALS iPSNs) displayed low expression of LSM12 and EPAC1. Lentiviral overexpression of LSM12 or EPAC1 indeed restored the RAN gradient, mitigated the pathogenic mislocalization of TDP-43, and suppressed caspase-3 activation for apoptosis in C9-ALS iPSNs. EPAC1 depletion biochemically dissociated RAN-importin ß1 from the cytoplasmic nuclear pore complex, thereby dissipating the nucleocytoplasmic RAN gradient essential for NCT. These findings define the LSM12-EPAC1 pathway as an important suppressor of the NCT-related pathologies in C9-ALS/FTD.


Assuntos
Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Proteína ran de Ligação ao GTP/metabolismo , Transporte Ativo do Núcleo Celular , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Núcleo Celular/metabolismo , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , AMP Cíclico/metabolismo , Citoplasma/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Poro Nuclear/metabolismo , Proteínas de Transporte Nucleocitoplasmático/genética
12.
Artigo em Russo | MEDLINE | ID: mdl-33081454

RESUMO

OBJECTIVE: To evaluate the frequency of C9orf72-associated frontotemporal dementia (FTD) in the Russian population and to study clinical features of GGGGCC-repeat expansion carriers. MATERIAL AND METHODS: Twenty-eight patients with FTD are included in the study: 15 with a behavioral variant of FTD (bvFTD) and 13 with a agrammatic/non-fluent variant of primary progressive aphasia (avPPA). The mean age was 62 years (34-80), the mean disease duration was 4 years (1-10). The positive family history was noted in 46% of cases. DNA diagnosis was performed using repeat-primed polymerase chain reaction. RESULTS: The frequency of the C9orf72 repeat expansion in patients with FTD was 14%, in patients with bvFTD 20%, in patients with avPPA 8%. The mean age of disease onset in the expansion carriers was 63 (55-75) years. The frequency of the C9orf72 repeats expansion in familial FTD cases was 31%, in sporadic cases 7%. bvFTD with parkinsonian syndrome was noted in two out of four cases, bvFTD with amyotrophic lateral sclerosis (ALS) was shown in one case, avPPA with ALS was shown in one case. One female patient with bvFTD with parkinsonian syndrome presented with cognitive fluctuations that required a differential diagnosis with Lewy body disease. CONCLUSION: This is the first study of the genetic structure of FTD in the Russian population. The prevalence and clinical characteristics of C9orf72-associated FTD were defined, in particular, the spectrum of motor symptoms was shown along with behavioral and aphasic disturbances. DNA diagnosis plays an important role in confirming the diagnosis and selection of patients for potential disease-modifying treatment.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/epidemiologia , Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Feminino , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/epidemiologia , Demência Frontotemporal/genética , Humanos , Pessoa de Meia-Idade , Proteínas/genética , Federação Russa/epidemiologia
13.
Proc Natl Acad Sci U S A ; 117(40): 25104-25115, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958650

RESUMO

Maintaining the fidelity of nascent peptide chain (NP) synthesis is essential for proteome integrity and cellular health. Ribosome-associated quality control (RQC) serves to resolve stalled translation, during which untemplated Ala/Thr residues are added C terminally to stalled peptide, as shown during C-terminal Ala and Thr addition (CAT-tailing) in yeast. The mechanism and biological effects of CAT-tailing-like activity in metazoans remain unclear. Here we show that CAT-tailing-like modification of poly(GR), a dipeptide repeat derived from amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD)-associated GGGGCC (G4C2) repeat expansion in C9ORF72, contributes to disease. We find that poly(GR) can act as a mitochondria-targeting signal, causing some poly(GR) to be cotranslationally imported into mitochondria. However, poly(GR) translation on mitochondrial surface is frequently stalled, triggering RQC and CAT-tailing-like C-terminal extension (CTE). CTE promotes poly(GR) stabilization, aggregation, and toxicity. Our genetic studies in Drosophila uncovered an important role of the mitochondrial protease YME1L in clearing poly(GR), revealing mitochondria as major sites of poly(GR) metabolism. Moreover, the mitochondria-associated noncanonical Notch signaling pathway impinges on the RQC machinery to restrain poly(GR) accumulation, at least in part through the AKT/VCP axis. The conserved actions of YME1L and noncanonical Notch signaling in animal models and patient cells support their fundamental involvement in ALS/FTD.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Proteínas de Drosophila/genética , Demência Frontotemporal/genética , Metaloendopeptidases/genética , Proteínas Mitocondriais/genética , Proteoma/genética , Receptores Notch/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Arginina/genética , Expansão das Repetições de DNA/genética , Modelos Animais de Doenças , Drosophila melanogaster/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Células HEK293 , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Biossíntese de Proteínas , Ribossomos/genética , Ribossomos/metabolismo , Transdução de Sinais/genética
15.
Nature ; 585(7824): 251-255, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32848248

RESUMO

Mutation of C9orf72 is the most prevalent defect associated with amyotrophic lateral sclerosis and frontotemporal degeneration1. Together with hexanucleotide-repeat expansion2,3, haploinsufficiency of C9orf72 contributes to neuronal dysfunction4-6. Here we determine the structure of the C9orf72-SMCR8-WDR41 complex by cryo-electron microscopy. C9orf72 and SMCR8 both contain longin and DENN (differentially expressed in normal and neoplastic cells) domains7, and WDR41 is a ß-propeller protein that binds to SMCR8 such that the whole structure resembles an eye slip hook. Contacts between WDR41 and the DENN domain of SMCR8 drive the lysosomal localization of the complex in conditions of amino acid starvation. The structure suggested that C9orf72-SMCR8 is a GTPase-activating protein (GAP), and we found that C9orf72-SMCR8-WDR41 acts as a GAP for the ARF family of small GTPases. These data shed light on the function of C9orf72 in normal physiology, and in amyotrophic lateral sclerosis and frontotemporal degeneration.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteínas Relacionadas à Autofagia/química , Proteína C9orf72/química , Proteína C9orf72/genética , Proteínas de Transporte/química , Microscopia Crioeletrônica , Demência Frontotemporal/genética , Haploinsuficiência , Complexos Multiproteicos/química , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Esclerose Amiotrófica Lateral/metabolismo , Proteínas Relacionadas à Autofagia/deficiência , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/ultraestrutura , Proteína C9orf72/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Transporte/ultraestrutura , Demência Frontotemporal/metabolismo , Humanos , Lisossomos/metabolismo , Modelos Moleculares , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/ultraestrutura , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação , Domínios Proteicos
17.
Nat Commun ; 11(1): 3354, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620797

RESUMO

Expansion of an intronic (GGGGCC)n repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here, we show that RNA decay mechanisms involving upstream frameshift 1 (UPF1), including nonsense-mediated decay (NMD), are inhibited in c9ALS/FTD brains and in cultured cells expressing either of two arginine-rich dipeptide repeats (R-DPRs), poly(GR) and poly(PR). Mechanistically, although R-DPRs cause the recruitment of UPF1 to stress granules, stress granule formation is independent of NMD inhibition. Instead, NMD inhibition is primarily a result from global translational repression caused by R-DPRs. Overexpression of UPF1, but none of its NMD-deficient mutants, enhanced the survival of neurons treated by R-DPRs, suggesting that R-DPRs cause neurotoxicity in part by inhibiting cellular RNA surveillance.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Demência Frontotemporal/genética , Degradação do RNAm Mediada por Códon sem Sentido , RNA Helicases/metabolismo , Transativadores/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Expansão das Repetições de DNA , Conjuntos de Dados como Assunto , Embrião de Mamíferos , Feminino , Lobo Frontal/patologia , Demência Frontotemporal/patologia , Humanos , Íntrons/genética , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Cultura Primária de Células , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , RNA-Seq , Transativadores/genética
18.
Neuron ; 107(6): 1124-1140.e11, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32673563

RESUMO

Through mechanisms that remain poorly defined, defects in nucleocytoplasmic transport and accumulations of specific nuclear-pore-complex-associated proteins have been reported in multiple neurodegenerative diseases, including C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS/FTD). Using super-resolution structured illumination microscopy, we have explored the mechanism by which nucleoporins are altered in nuclei isolated from C9orf72 induced pluripotent stem-cell-derived neurons (iPSNs). Of the 23 nucleoporins evaluated, we observed a reduction in a subset of 8, including key components of the nuclear pore complex scaffold and the transmembrane nucleoporin POM121. Reduction in POM121 appears to initiate a decrease in the expression of seven additional nucleoporins, ultimately affecting the localization of Ran GTPase and subsequent cellular toxicity in C9orf72 iPSNs. Collectively, our data suggest that the expression of expanded C9orf72 ALS/FTD repeat RNA alone affects nuclear POM121 expression in the initiation of a pathological cascade affecting nucleoporin levels within neuronal nuclei and ultimately downstream neuronal survival.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Proteína C9orf72/genética , Demência Frontotemporal/metabolismo , Glicoproteínas de Membrana/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Transporte Ativo do Núcleo Celular , Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/metabolismo , Células Cultivadas , Demência Frontotemporal/genética , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Glicoproteínas de Membrana/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Poro Nuclear/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
19.
Nature ; 582(7810): 89-94, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32483373

RESUMO

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3-9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6-9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics-as well as transplanting gut microflora from a protective environment-attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.


Assuntos
Proteína C9orf72/genética , Microbioma Gastrointestinal/fisiologia , Gliose/microbiologia , Gliose/patologia , Inflamação/genética , Inflamação/microbiologia , Medula Espinal/patologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Antibacterianos/farmacologia , Autoimunidade/efeitos dos fármacos , Autoimunidade/genética , Autoimunidade/imunologia , Movimento Celular/efeitos dos fármacos , Citocinas/imunologia , Transplante de Microbiota Fecal , Feminino , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Gliose/genética , Gliose/prevenção & controle , Inflamação/patologia , Inflamação/prevenção & controle , Mutação com Perda de Função/genética , Masculino , Camundongos , Microglia/imunologia , Microglia/microbiologia , Microglia/patologia , Medula Espinal/imunologia , Medula Espinal/microbiologia , Taxa de Sobrevida
20.
Neuron ; 107(2): 292-305.e6, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32375063

RESUMO

GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Dipeptídeos/genética , Demência Frontotemporal/genética , Proteínas Mutantes Quiméricas/genética , Ataxias Espinocerebelares/genética , Sequência de Aminoácidos , Animais , Animais Recém-Nascidos , Elementos Antissenso (Genética)/genética , Expansão das Repetições de DNA , Feminino , Humanos , Íntrons/genética , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Sequências Repetitivas de Ácido Nucleico
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