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1.
Cell ; 185(13): 2201-2203, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35750028

RESUMO

The ε4 variant in the APOE gene is the strongest genetic risk factor for Alzheimer's disease. How does this gene impact different cell types in the brain to increase disease risk? In this issue of Cell, TCW and colleagues report APOE-driven cell-type-specific changes that may contribute to Alzheimer's disease risk.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Apolipoproteínas E/metabolismo , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Encéfalo , Humanos , Fatores de Risco
2.
Cell ; 184(16): 4284-4298.e27, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34233164

RESUMO

Many organisms evolved strategies to survive desiccation. Plant seeds protect dehydrated embryos from various stressors and can lay dormant for millennia. Hydration is the key trigger to initiate germination, but the mechanism by which seeds sense water remains unresolved. We identified an uncharacterized Arabidopsis thaliana prion-like protein we named FLOE1, which phase separates upon hydration and allows the embryo to sense water stress. We demonstrate that biophysical states of FLOE1 condensates modulate its biological function in vivo in suppressing seed germination under unfavorable environments. We find intragenic, intraspecific, and interspecific natural variation in FLOE1 expression and phase separation and show that intragenic variation is associated with adaptive germination strategies in natural populations. This combination of molecular, organismal, and ecological studies uncovers FLOE1 as a tunable environmental sensor with direct implications for the design of drought-resistant crops, in the face of climate change.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/crescimento & desenvolvimento , Germinação , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Príons/metabolismo , Sementes/crescimento & desenvolvimento , Água/metabolismo , Arabidopsis/genética , Arabidopsis/ultraestrutura , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/ultraestrutura , Desidratação , Imageamento Tridimensional , Peptídeos e Proteínas de Sinalização Intercelular/química , Mutação/genética , Dormência de Plantas , Plantas Geneticamente Modificadas , Domínios Proteicos , Isoformas de Proteínas/metabolismo , Sementes/ultraestrutura
3.
Cell ; 184(3): 689-708.e20, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33482083

RESUMO

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.


Assuntos
Proteína C9orf72/metabolismo , Expansão das Repetições de DNA/genética , Degeneração Neural/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Axônios/metabolismo , Proteína C9orf72/genética , Morte Celular , Células Cultivadas , Córtex Cerebral/patologia , Cromatina/metabolismo , Dano ao DNA , Modelos Animais de Doenças , Drosophila , Camundongos Endogâmicos C57BL , Degeneração Neural/patologia , Estabilidade Proteica , Transcrição Gênica , Proteínas Supressoras de Tumor/metabolismo
4.
Cell ; 173(4): 958-971.e17, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29628143

RESUMO

Defects in nucleocytoplasmic transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of ALS/FTD. Furthermore, nucleocytoplasmic transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts nucleocytoplasmic transport. Here, we show that cellular stress disrupts nucleocytoplasmic transport by localizing critical nucleocytoplasmic transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis. Importantly, inhibiting stress granule assembly, such as by knocking down Ataxin-2, suppresses nucleocytoplasmic transport defects as well as neurodegeneration in C9ORF72-mediated ALS/FTD. Our findings identify a link between stress granule assembly and nucleocytoplasmic transport, two fundamental cellular processes implicated in the pathogenesis of C9ORF72-mediated ALS/FTD and other neurodegenerative diseases.


Assuntos
Transporte Ativo do Núcleo Celular/fisiologia , Esclerose Lateral Amiotrófica/patologia , Ataxina-2/metabolismo , Proteína C9orf72/genética , Demência Frontotemporal/patologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Idoso , Esclerose Lateral Amiotrófica/metabolismo , Arsenitos/toxicidade , Ataxina-2/antagonistas & inibidores , Ataxina-2/genética , Proteína C9orf72/metabolismo , Expansão das Repetições de DNA/genética , Feminino , Demência Frontotemporal/metabolismo , Células HEK293 , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Compostos de Sódio/toxicidade , alfa Carioferinas/antagonistas & inibidores , alfa Carioferinas/genética , alfa Carioferinas/metabolismo , beta Carioferinas/antagonistas & inibidores , beta Carioferinas/genética , beta Carioferinas/metabolismo , Proteína ran de Ligação ao GTP/antagonistas & inibidores , Proteína ran de Ligação ao GTP/genética , Proteína ran de Ligação ao GTP/metabolismo
5.
Cell ; 173(3): 677-692.e20, 2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29677512

RESUMO

RNA-binding proteins (RBPs) with prion-like domains (PrLDs) phase transition to functional liquids, which can mature into aberrant hydrogels composed of pathological fibrils that underpin fatal neurodegenerative disorders. Several nuclear RBPs with PrLDs, including TDP-43, FUS, hnRNPA1, and hnRNPA2, mislocalize to cytoplasmic inclusions in neurodegenerative disorders, and mutations in their PrLDs can accelerate fibrillization and cause disease. Here, we establish that nuclear-import receptors (NIRs) specifically chaperone and potently disaggregate wild-type and disease-linked RBPs bearing a NLS. Karyopherin-ß2 (also called Transportin-1) engages PY-NLSs to inhibit and reverse FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2 fibrillization, whereas Importin-α plus Karyopherin-ß1 prevent and reverse TDP-43 fibrillization. Remarkably, Karyopherin-ß2 dissolves phase-separated liquids and aberrant fibrillar hydrogels formed by FUS and hnRNPA1. In vivo, Karyopherin-ß2 prevents RBPs with PY-NLSs accumulating in stress granules, restores nuclear RBP localization and function, and rescues degeneration caused by disease-linked FUS and hnRNPA2. Thus, NIRs therapeutically restore RBP homeostasis and mitigate neurodegeneration.


Assuntos
Transporte Ativo do Núcleo Celular , Príons/química , Proteínas de Ligação a RNA/química , Receptores Citoplasmáticos e Nucleares/química , Adulto , Idoso , Animais , Citoplasma/química , Proteínas de Ligação a DNA/química , Drosophila melanogaster , Feminino , Proteínas de Fluorescência Verde/química , Células HEK293 , Células HeLa , Homeostase , Humanos , Carioferinas/química , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/química , Mutação , Doenças Neurodegenerativas/patologia , Domínios Proteicos , Proteína EWS de Ligação a RNA/química , Fatores Associados à Proteína de Ligação a TATA/química , beta Carioferinas/química
6.
Mol Cell ; 83(12): 2020-2034.e6, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37295429

RESUMO

Biomolecular condensation underlies the biogenesis of an expanding array of membraneless assemblies, including stress granules (SGs), which form under a variety of cellular stresses. Advances have been made in understanding the molecular grammar of a few scaffold proteins that make up these phases, but how the partitioning of hundreds of SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, an SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14 aa sequence that acts as a condensation switch and is conserved across the eukaryote lineage. We identify poly(A)-binding proteins as unconventional RNA-dependent chaperones that control this regulatory switch. Our results uncover a hierarchy of cis and trans interactions that fine-tune ataxin-2 condensation and reveal an unexpected molecular function for ancient poly(A)-binding proteins as regulators of biomolecular condensate proteins. These findings may inspire approaches to therapeutically target aberrant phases in disease.


Assuntos
Ataxina-2 , Doenças Neurodegenerativas , Humanos , Ataxina-2/genética , Proteína I de Ligação a Poli(A) , Doenças Neurodegenerativas/metabolismo , Condensados Biomoleculares
7.
Mol Cell ; 82(22): 4194-4196, 2022 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-36400005

RESUMO

In this issue of Molecular Cell, Gropp et al. identify how the cellular background affects whether or not the Huntington's disease protein will form toxic pathological aggregates, providing insight into selective neuronal vulnerability in neurodegenerative disease.


Assuntos
Doença de Huntington , Doenças Neurodegenerativas , Humanos , Doença de Huntington/patologia , Neurônios/metabolismo
8.
Cell ; 154(6): 1182-4, 2013 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-24034239

RESUMO

Alzheimer's disease (AD) is associated with the deposition of ß-amyloid (Aß) plaques in the brain. In this issue, by cleverly processing patient samples, Lu et al. define a novel structural model of Aß fibrils from AD brain, revealing surprising differences from in vitro fibrils. These findings may lead to structure-specific inhibitors and more selective amyloid-imaging methods.


Assuntos
Doença de Alzheimer/patologia , Amiloide/química , Encéfalo/patologia , Feminino , Humanos
9.
Nature ; 603(7899): 124-130, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35197626

RESUMO

A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2-4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.


Assuntos
Esclerose Lateral Amiotrófica , Demência Frontotemporal , Esclerose Lateral Amiotrófica/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Éxons/genética , Demência Frontotemporal/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Neurônios Motores/patologia , Proteínas do Tecido Nervoso
10.
Mol Cell ; 78(2): 193-194, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32302539

RESUMO

Heterochromatin protein 1 (HP1) has been proposed to drive heterochromatin formation by liquid-liquid phase separation. In this issue of Molecular Cell, however, Erdel et al. establish that heterochromatin can adopt digital compaction states that are independent of HP1 phase separation.


Assuntos
Proteínas Cromossômicas não Histona , Heterocromatina , Animais , Montagem e Desmontagem da Cromatina , Homólogo 5 da Proteína Cromobox , DNA , Camundongos
11.
Nature ; 599(7883): 102-107, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34616039

RESUMO

Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease1-6. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor5,6. Notably, instead of a protein, saturated lipids contained in APOE and APOJ lipoparticles mediate astrocyte-induced toxicity. Eliminating the formation of long-chain saturated lipids by astrocyte-specific knockout of the saturated lipid synthesis enzyme ELOVL1 mitigates astrocyte-mediated toxicity in vitro as well as in a model of acute axonal injury in vivo. These results suggest a mechanism by which astrocytes kill cells in the central nervous system.


Assuntos
Astrócitos/química , Astrócitos/metabolismo , Morte Celular/efeitos dos fármacos , Lipídeos/química , Lipídeos/toxicidade , Animais , Meios de Cultivo Condicionados/química , Meios de Cultivo Condicionados/toxicidade , Elongases de Ácidos Graxos/deficiência , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Feminino , Técnicas de Inativação de Genes , Masculino , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurotoxinas/química , Neurotoxinas/toxicidade
12.
Trends Biochem Sci ; 47(1): 1-2, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34654581

RESUMO

A recent study by Huang et al. unexpectedly uncovered that DAXX moonlights as a booster of protein folding, including counteracting aggregation of tumor suppressor p53. Since p53 aggregation is a common hallmark of cancer, this finding provides a potential pathway to therapeutically reactivate p53 signaling and halt tumor progression.


Assuntos
Neoplasias , Proteínas Nucleares , Proteínas Correpressoras/metabolismo , Humanos , Chaperonas Moleculares/metabolismo , Proteínas Nucleares/metabolismo , Dobramento de Proteína , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
13.
Mol Cell ; 71(5): 649-651, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30193092

RESUMO

In this issue of Molecular Cell, McGurk et al. (2018) identify how poly(ADP-ribose) binding tunes the phase behavior of the ALS disease protein TDP-43, uncovering the molecular events underlying its aggregation in disease and illuminating a novel therapeutic target.


Assuntos
Esclerose Lateral Amiotrófica , Poli Adenosina Difosfato Ribose , Proteínas de Ligação a DNA , Humanos , Açúcares
14.
Trends Genet ; 38(9): 904-919, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35487823

RESUMO

Motor neurons are a remarkably powerful cell type in the central nervous system. They innervate and control the contraction of virtually every muscle in the body and their dysfunction underlies numerous neuromuscular diseases. Some motor neurons seem resistant to degeneration whereas others are vulnerable. The intrinsic heterogeneity of motor neurons in adult organisms has remained elusive. The development of high-throughput single-cell transcriptomics has changed the paradigm, empowering rapid isolation and profiling of motor neuron nuclei, revealing remarkable transcriptional diversity within the skeletal and autonomic nervous systems. Here, we discuss emerging technologies for defining motor neuron heterogeneity in the adult motor system as well as implications for disease and spinal cord injury. We establish a roadmap for future applications of emerging techniques - such as epigenetic profiling, spatial RNA sequencing, and single-cell somatic mutational profiling to adult motor neurons, which will revolutionize our understanding of the healthy and degenerating adult motor system.


Assuntos
Esclerose Lateral Amiotrófica , Adulto , Esclerose Lateral Amiotrófica/genética , Animais , Modelos Animais de Doenças , Humanos , Neurônios Motores/metabolismo , Medula Espinal , Transcriptoma/genética
15.
Brain ; 147(9): 3032-3047, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-38940350

RESUMO

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.


Assuntos
Encéfalo , Degeneração Lobar Frontotemporal , Humanos , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Masculino , Feminino , Idoso , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Pessoa de Meia-Idade , Proteínas tau/genética , Proteínas tau/metabolismo , Atrofia/genética , Animais , Evolução Molecular , Expressão Gênica/genética
16.
J Neurosci ; 43(2): 333-345, 2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36446586

RESUMO

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects of C9orf72 HRE and clinical diagnosis (n = 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity (n = 114 individuals, male and female). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element L1HS L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated that C9orf72 levels relate to clinical severity, and identified marked derepression of TEs, including L1HS, which predicted atrophy of FTD-relevant thalamic nuclei.SIGNIFICANCE STATEMENT Pathogenic repeat expansion in C9orf72 is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements-genetic elements typically repressed in the human genome-in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information.


Assuntos
Esclerose Lateral Amiotrófica , Demência Frontotemporal , Humanos , Masculino , Feminino , Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Proteína C9orf72/genética , Elementos de DNA Transponíveis , Atrofia
17.
Am J Hum Genet ; 107(3): 445-460, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32750315

RESUMO

Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater repeat copy number is significantly enriched in three independent cohorts of individuals with sporadic amyotrophic lateral sclerosis (ALS). Each unit of the repeat forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells. We leveraged its remarkable sequence variability to align the repeat in 288 samples and uncover its mechanism of expansion. We found that the repeat expands in the 3'-5' direction, in groups of repeat units divisible by two. The expansion patterns we observed were consistent with duplication events, and a replication error called template switching. We also observed that the VNTR is expanded in both Denisovan and Neanderthal genomes but is fixed at one copy or fewer in non-human primates. Evaluating the repeat in 1000 Genomes Project samples reveals that some repeat segments are solely present or absent in certain geographic populations. The large size of the repeat unit in this VNTR, along with our multiplexed sequencing strategy, provides an unprecedented opportunity to study mechanisms of repeat expansion, and a framework for evaluating the roles of VNTRs in human evolution and disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Esclerose Lateral Amiotrófica/genética , Evolução Molecular , Sequências de Repetição em Tandem/genética , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Esclerose Lateral Amiotrófica/patologia , Expansão das Repetições de DNA/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Masculino , Repetições Minissatélites/genética , Fenótipo , Especificidade da Espécie
18.
Nature ; 544(7650): 367-371, 2017 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-28405022

RESUMO

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that is characterized by motor neuron loss and that leads to paralysis and death 2-5 years after disease onset. Nearly all patients with ALS have aggregates of the RNA-binding protein TDP-43 in their brains and spinal cords, and rare mutations in the gene encoding TDP-43 can cause ALS. There are no effective TDP-43-directed therapies for ALS or related TDP-43 proteinopathies, such as frontotemporal dementia. Antisense oligonucleotides (ASOs) and RNA-interference approaches are emerging as attractive therapeutic strategies in neurological diseases. Indeed, treatment of a rat model of inherited ALS (caused by a mutation in Sod1) with ASOs against Sod1 has been shown to substantially slow disease progression. However, as SOD1 mutations account for only around 2-5% of ALS cases, additional therapeutic strategies are needed. Silencing TDP-43 itself is probably not appropriate, given its critical cellular functions. Here we present a promising alternative therapeutic strategy for ALS that involves targeting ataxin-2. A decrease in ataxin-2 suppresses TDP-43 toxicity in yeast and flies, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase risk of ALS. We used two independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy. First, we crossed ataxin-2 knockout mice with TDP-43 (also known as TARDBP) transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP-43, markedly increased survival and improved motor function. Second, in a more therapeutically applicable approach, we administered ASOs targeting ataxin-2 to the central nervous system of TDP-43 transgenic mice. This single treatment markedly extended survival. Because TDP-43 aggregation is a component of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic strategy.


Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/terapia , Ataxina-2/deficiência , Proteínas de Ligação a DNA/metabolismo , Longevidade , Oligonucleotídeos Antissenso/uso terapêutico , Agregação Patológica de Proteínas/terapia , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Ataxina-2/genética , Sistema Nervoso Central/metabolismo , Grânulos Citoplasmáticos/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Destreza Motora/fisiologia , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/genética , Agregação Patológica de Proteínas/genética , Estresse Fisiológico , Análise de Sobrevida
19.
Genome Res ; 29(5): 809-818, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30940688

RESUMO

Large-scale sequencing efforts in amyotrophic lateral sclerosis (ALS) have implicated novel genes using gene-based collapsing methods. However, pathogenic mutations may be concentrated in specific genic regions. To address this, we developed two collapsing strategies: One focuses rare variation collapsing on homology-based protein domains as the unit for collapsing, and the other is a gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against missense variation on said domains. The application of these two collapsing methods to 3093 ALS cases and 8186 controls of European ancestry, and also 3239 cases and 11,808 controls of diversified populations, pinpoints risk regions of ALS genes, including SOD1, NEK1, TARDBP, and FUS While not clearly implicating novel ALS genes, the new analyses not only pinpoint risk regions in known genes but also highlight candidate genes as well.


Assuntos
Esclerose Lateral Amiotrófica/genética , Análise Mutacional de DNA/métodos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Feminino , Variação Genética , Humanos , Masculino , Mutação , Quinase 1 Relacionada a NIMA/genética , Domínios Proteicos/genética , Proteína FUS de Ligação a RNA/genética , Fatores de Risco , Superóxido Dismutase-1/genética , População Branca/genética , Sequenciamento do Exoma/métodos
20.
Nature ; 539(7628): 207-216, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27830778

RESUMO

Parkinson's disease is a debilitating, age-associated movement disorder. A central aspect of the pathophysiology of Parkinson's disease is the progressive demise of midbrain dopamine neurons and their axonal projections, but the underlying causes of this loss are unclear. Advances in genetics and experimental model systems have illuminated an important role for defects in intracellular transport pathways to lysosomes. The accumulation of altered proteins and damaged mitochondria, particularly at axon terminals, ultimately might overwhelm the capacity of intracellular disposal mechanisms. Cell-extrinsic mechanisms, including inflammation and prion-like spreading, are proposed to have both protective and deleterious functions in Parkinson's disease.


Assuntos
Doença de Parkinson , Animais , Transporte Biológico/genética , Endocitose , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Lisossomos/metabolismo , Modelos Biológicos , Terapia de Alvo Molecular , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Príons/metabolismo , Vesículas Sinápticas/metabolismo , alfa-Sinucleína/metabolismo
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