RESUMO
INTRODUCTION/AIMS: Since 2016, six states have legalized physician-hastened death (PHD). Neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), are common diagnoses for patients who use PHD, but how patients with ALS view PHD in California has not been systematically studied. We aimed to quantify how many patients with ALS and their caregivers have considered PHD and to assess reasons to consider using or not using it. METHODS: This is a cross-sectional study at one ALS center surveying patients with ALS and their caregivers. Data on disease characteristics, demographics, quality of life, and depression were also collected. Descriptive statistics were used to analyze the data. Qualitative data were also collected and analyzed. Patients were followed up longitudinally to assess if they died or if they used PHD. RESULTS: A small majority of ALS patients surveyed had considered or would consider using PHD (16/30). Patients most commonly described having intolerable symptoms, being a burden on their loved ones, and losing independence as reasons to consider using PHD. Many patients shared that "their life has purpose" and "they are making the most of their lives" as to why they are not considering PHD. Considering PHD was not related to disease severity or depression. On longitudinal follow-up, 10 of the 30 patients have died, and none have used PHD. DISCUSSION: Pursuing PHD is a personal decision for each individual patient. This study shows that considering PHD is relatively common in ALS patients, independent of disease severity or presence of depression.
Assuntos
Esclerose Lateral Amiotrófica/psicologia , Cuidadores/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Participação do Paciente/psicologia , Papel do Médico/psicologia , Suicídio Assistido/psicologia , Adaptação Psicológica/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/terapia , California/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Participação do Paciente/métodosRESUMO
Progressive synapse loss is an inevitable and insidious part of age-related neurodegenerative disease. Typically, synapse loss precedes symptoms of cognitive and motor decline. This suggests the existence of compensatory mechanisms that can temporarily counteract the effects of ongoing neurodegeneration. Here, we demonstrate that presynaptic homeostatic plasticity (PHP) is induced at degenerating neuromuscular junctions, mediated by an evolutionarily conserved activity of presynaptic ENaC channels in both Drosophila and mouse. To assess the consequence of eliminating PHP in a mouse model of ALS-like degeneration, we generated a motoneuron-specific deletion of Scnn1a, encoding the ENaC channel alpha subunit. We show that Scnn1a is essential for PHP without adversely affecting baseline neural function or lifespan. However, Scnn1a knockout in a degeneration-causing mutant background accelerated motoneuron loss and disease progression to twice the rate observed in littermate controls with intact PHP. We propose a model of neuroprotective homeostatic plasticity, extending organismal lifespan and health span.
Assuntos
Canais Epiteliais de Sódio/metabolismo , Homeostase/fisiologia , Plasticidade Neuronal/fisiologia , Neuroproteção/fisiologia , Terminações Pré-Sinápticas/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Drosophila melanogaster , Camundongos , Camundongos Knockout , Junção Neuromuscular/metabolismoRESUMO
Presynaptic homeostatic plasticity stabilizes information transfer at synaptic connections in organisms ranging from insect to human. By analogy with principles of engineering and control theory, the molecular implementation of PHP is thought to require postsynaptic signaling modules that encode homeostatic sensors, a set point, and a controller that regulates transsynaptic negative feedback. The molecular basis for these postsynaptic, homeostatic signaling elements remains unknown. Here, an electrophysiology-based screen of the Drosophila kinome and phosphatome defines a postsynaptic signaling platform that includes a required function for PI3K-cII, PI3K-cIII and the small GTPase Rab11 during the rapid and sustained expression of PHP. We present evidence that PI3K-cII localizes to Golgi-derived, clathrin-positive vesicles and is necessary to generate an endosomal pool of PI(3)P that recruits Rab11 to recycling endosomal membranes. A morphologically distinct subdivision of this platform concentrates postsynaptically where we propose it functions as a homeostatic controller for retrograde, trans-synaptic signaling.
Assuntos
Classe II de Fosfatidilinositol 3-Quinases/metabolismo , Plasticidade Neuronal , Terminações Pré-Sinápticas/fisiologia , Transdução de Sinais , Animais , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Drosophila , Proteínas de Drosophila/metabolismo , Fenômenos Eletrofisiológicos , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
Lysosomes are classically viewed as vesicular structures to which cargos are delivered for degradation. Here, we identify a network of dynamic, tubular lysosomes that extends throughout Drosophila muscle, in vivo. Live imaging reveals that autophagosomes merge with tubular lysosomes and that lysosomal membranes undergo extension, retraction, fusion and fission. The dynamics and integrity of this tubular lysosomal network requires VCP, an AAA-ATPase that, when mutated, causes degenerative diseases of muscle, bone and neurons. We show that human VCP rescues the defects caused by loss of Drosophila VCP and overexpression of disease relevant VCP transgenes dismantles tubular lysosomes, linking tubular lysosome dysfunction to human VCP-related diseases. Finally, disruption of tubular lysosomes correlates with impaired autophagosome-lysosome fusion, increased cytoplasmic poly-ubiquitin aggregates, lipofuscin material, damaged mitochondria and impaired muscle function. We propose that VCP sustains sarcoplasmic proteostasis, in part, by controlling the integrity of a dynamic tubular lysosomal network.
Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/fisiologia , Lisossomos/metabolismo , Músculos/fisiologia , Músculos/ultraestrutura , Biogênese de Organelas , Animais , Drosophila/enzimologia , Drosophila/metabolismo , Teste de Complementação Genética , Humanos , Fagossomos/metabolismo , Proteína com ValosinaRESUMO
At synapses in organisms ranging from fly to human, a decrease in postsynaptic neurotransmitter receptor function elicits a homeostatic increase in presynaptic release that restores baseline synaptic efficacy. This process, termed presynaptic homeostasis, requires a retrograde, trans-synaptic signal of unknown identity. In a forward genetic screen for homeostatic plasticity genes, we identified multiplexin. Multiplexin is the Drosophila homolog of Collagen XV/XVIII, a matrix protein that can be proteolytically cleaved to release Endostatin, an antiangiogenesis signaling factor. Here we demonstrate that Multiplexin is required for normal calcium channel abundance, presynaptic calcium influx, and neurotransmitter release. Remarkably, Endostatin has a specific activity, independent of baseline synapse development, that is required for the homeostatic modulation of presynaptic calcium influx and neurotransmitter release. Our data support a model in which proteolytic release of Endostatin signals trans-synaptically, acting in concert with the presynaptic CaV2.1 calcium channel, to promote presynaptic homeostasis.
Assuntos
Cálcio/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Colágeno/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Endostatinas/metabolismo , Homeostase/fisiologia , Plasticidade Neuronal/fisiologia , Neurotransmissores/metabolismo , Animais , Canais de Cálcio/metabolismo , Humanos , Transdução de Sinais/fisiologia , Sinapses/metabolismoRESUMO
Chromatin modifiers regulate lifespan in several organisms, raising the question of whether changes in chromatin states in the parental generation could be incompletely reprogrammed in the next generation and thereby affect the lifespan of descendants. The histone H3 lysine 4 trimethylation (H3K4me3) complex, composed of ASH-2, WDR-5 and the histone methyltransferase SET-2, regulates Caenorhabditis elegans lifespan. Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5 or SET-2 in the parental generation extend the lifespan of descendants up until the third generation. The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendants. Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression. Thus, manipulation of specific chromatin modifiers only in parents can induce an epigenetic memory of longevity in descendants.
Assuntos
Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Epigênese Genética/genética , Padrões de Herança , Longevidade/genética , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Cromatina/metabolismo , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona-Lisina N-Metiltransferase/deficiência , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas , Longevidade/fisiologia , Masculino , Metilação , Mutação/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Linhagem , Proteína 2 de Ligação ao Retinoblastoma/genética , Proteína 2 de Ligação ao Retinoblastoma/metabolismoRESUMO
Aging is accompanied by alterations in epigenetic marks that control chromatin states, including histone acetylation and methylation. Enzymes that reversibly affect histone marks associated with active chromatin have recently been found to regulate aging in Caenorhabditis elegans. However, relatively little is known about the importance for aging of histone marks associated with repressed chromatin. Here, we use a targeted RNAi screen in C. elegans to identify four histone demethylases that significantly regulate worm lifespan, UTX-1, RBR-2, LSD-1, and T26A5.5. Interestingly, UTX-1 belongs to a conserved family of histone demethylases specific for lysine 27 of histone H3 (H3K27me3), a mark associated with repressed chromatin. Both utx-1 knockdown and heterozygous mutation of utx-1 extend lifespan and increase the global levels of the H3K27me3 mark in worms. The H3K27me3 mark significantly drops in somatic cells during the normal aging process. UTX-1 regulates lifespan independently of the presence of the germline, but in a manner that depends on the insulin-FoxO signaling pathway. These findings identify the H3K27me3 histone demethylase UTX-1 as a novel regulator of worm lifespan in somatic cells.
Assuntos
Caenorhabditis elegans/metabolismo , Cromatina/metabolismo , Regulação da Expressão Gênica , Histona Desmetilases/metabolismo , Histonas/metabolismo , Longevidade , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo , Animais , Biomarcadores/metabolismo , Western Blotting , Caenorhabditis elegans/genética , Cromatina/genética , Técnicas de Silenciamento de Genes , Células Germinativas/metabolismo , Ensaios de Triagem em Larga Escala , Histona Desmetilases/genética , Histonas/genética , Insulina/metabolismo , Metilação , Reação em Cadeia da Polimerase , Interferência de RNA , Fatores de Transcrição/genéticaRESUMO
The plasticity of ageing suggests that longevity may be controlled epigenetically by specific alterations in chromatin state. The link between chromatin and ageing has mostly focused on histone deacetylation by the Sir2 family, but less is known about the role of other histone modifications in longevity. Histone methylation has a crucial role in development and in maintaining stem cell pluripotency in mammals. Regulators of histone methylation have been associated with ageing in worms and flies, but characterization of their role and mechanism of action has been limited. Here we identify the ASH-2 trithorax complex, which trimethylates histone H3 at lysine 4 (H3K4), as a regulator of lifespan in Caenorhabditis elegans in a directed RNA interference (RNAi) screen in fertile worms. Deficiencies in members of the ASH-2 complex-ASH-2 itself, WDR-5 and the H3K4 methyltransferase SET-2-extend worm lifespan. Conversely, the H3K4 demethylase RBR-2 is required for normal lifespan, consistent with the idea that an excess of H3K4 trimethylation-a mark associated with active chromatin-is detrimental for longevity. Lifespan extension induced by ASH-2 complex deficiency requires the presence of an intact adult germline and the continuous production of mature eggs. ASH-2 and RBR-2 act in the germline, at least in part, to regulate lifespan and to control a set of genes involved in lifespan determination. These results indicate that the longevity of the soma is regulated by an H3K4 methyltransferase/demethylase complex acting in the C. elegans germline.