Abstract:
:The toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease. Accordingly, neurons invest considerable cellular resources in chaperones, protein degradation, autophagy and mitophagy to maintain proteostasis and mitochondrial quality. Complicating the challenges of neuroprotection, misfolded human disease proteins and mitochondria can move into neighbouring cells via unknown mechanisms, which may promote pathological spread. Here we show that adult neurons from Caenorhabditis elegans extrude large (approximately 4 μm) membrane-surrounded vesicles called exophers that can contain protein aggregates and organelles. Inhibition of chaperone expression, autophagy or the proteasome, in addition to compromising mitochondrial quality, enhances the production of exophers. Proteotoxically stressed neurons that generate exophers subsequently function better than similarly stressed neurons that did not produce exophers. The extruded exopher transits through surrounding tissue in which some contents appear degraded, but some non-degradable materials can subsequently be found in more remote cells, suggesting secondary release. Our observations suggest that exopher-genesis is a potential response to rid cells of neurotoxic components when proteostasis and organelle function are challenged. We propose that exophers are components of a conserved mechanism that constitutes a fundamental, but formerly unrecognized, branch of neuronal proteostasis and mitochondrial quality control, which, when dysfunctional or diminished with age, might actively contribute to pathogenesis in human neurodegenerative disease and brain ageing.
journal_name
Naturejournal_title
Natureauthors
Melentijevic I,Toth ML,Arnold ML,Guasp RJ,Harinath G,Nguyen KC,Taub D,Parker JA,Neri C,Gabel CV,Hall DH,Driscoll Mdoi
10.1038/nature21362subject
Has Abstractpub_date
2017-02-16 00:00:00pages
367-371issue
7641eissn
0028-0836issn
1476-4687pii
nature21362journal_volume
542pub_type
杂志文章相关文献
NATURE文献大全abstract::Leks have traditionally been considered as arenas where males compete to attract females and secure matings. Thus, direct fitness benefits mediated through competition between males to fertilize females have been considered to be the primary force driving the evolution of lekking behaviour. Inclusive fitness benefits ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35042562
更新日期:2000-11-16 00:00:00
abstract::Greek speakers say "omicronupsilonrho", Germans "schwanz" and the French "queue" to describe what English speakers call a 'tail', but all of these languages use a related form of 'two' to describe the number after one. Among more than 100 Indo-European languages and dialects, the words for some meanings (such as 'tail...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature06176
更新日期:2007-10-11 00:00:00
abstract::Wilms' tumour (WT), a paediatric renal neoplasm, affect approximately 1 in 10,000 children. One or both kidneys can be affected and 5-10% of tumours are bilateral. Most tumours occur sporadically; however, around 1% of the cases are familial, with siblings or cousins most often being affected. Familial cases are more ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/336377a0
更新日期:1988-11-24 00:00:00
abstract::B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. He...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09454
更新日期:2010-09-30 00:00:00
abstract::The type III secretion (T3S) injectisome is a specialized protein nanomachine that is critical for the pathogenicity of many Gram-negative bacteria, including purveyors of plague, typhoid fever, whooping cough, sexually transmitted infections and major nosocomial infections. This syringe-shaped 3.5-MDa macromolecular ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature20576
更新日期:2016-12-22 00:00:00
abstract::The recent discovery that the human T-cell lymphoma leukemia virus (HTLV) may be the agent of transmission of T-cell lymphoid malignancies raises ethical questions for blood transfusion services. The effort to avoid use of contaminated blood is dependent to a large extent on the willingness and ability of donors to g...
journal_title:Nature
pub_type: 新闻
doi:10.1038/302567a0
更新日期:1983-04-14 00:00:00
abstract::Templates are widely used to arrange molecular components so they can be covalently linked into complex molecules that are not readily accessible by classical synthetic methods. Nature uses sophisticated templates such as the ribosome, whereas chemists use simple ions or small molecules. But as we tackle the synthesis...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09683
更新日期:2011-01-06 00:00:00
abstract::Over the past 50 years there has been much speculation about the energetic cost of swimming and wave-riding by dolphins. When aligned properly in front of the bow of moving ships in the stern wake of small boats, on wind waves, and even in the wake of larger cetaceans, the animals appear to move effortlessly through t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/355821a0
更新日期:1992-02-27 00:00:00
abstract::Three-wave mixing in nonlinear materials--the interaction of two light waves to produce a third--is a convenient way of generating new optical frequencies from common laser sources. However, the resulting optical conversion yield is generally poor, because the relative phases of the three interacting waves change cont...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature03027
更新日期:2004-11-18 00:00:00
abstract::The alpha-like and beta-like globin genes have provided a paradigm for the study of molecular evolution and regulation of multigene families in eukaryotes. The human alpha-globin gene cluster, which is on chromosome 16 (ref. 1), consists of six genes arranged in the order 5'-zeta(embryonic)-psi zeta-psi alpha 2-psi al...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/321785a0
更新日期:1986-06-19 00:00:00
abstract::Synapsin I is a neuron-specific phosphoprotein localized to the cytoplasmic surface of synaptic vesicles. This phosphoprotein is a major substrate for cyclic AMP-dependent and calcium/calmodulin-dependent protein kinases. Its state of phosphorylation can be altered both in vivo and in vitro by a variety of physiologic...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/326704a0
更新日期:1987-04-16 00:00:00
abstract::B LYMPHOCYTES are key participants in the immune response because of their specificity, their ability to take up and present antigens to T cells, and their capacity to differentiate into antibody-secreting cells. To limit reactivity to self antigens, autospecific B cells can be functionally inactivated or deleted. Dev...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/354308a0
更新日期:1991-11-28 00:00:00
abstract::Transport of calcium ions across membranes and against a thermodynamic gradient is essential to many biological processes, including muscle contraction, the citric acid cycle, glycogen metabolism, release of neurotransmitters, vision, biological signal transduction and immune response. Synthetic systems that transport...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature01209
更新日期:2002-11-28 00:00:00
abstract::The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects suc...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature19079
更新日期:2016-08-11 00:00:00
abstract::Haem is essential for living organisms, functioning as a crucial element in the redox-sensitive reaction centre in haemproteins. During the biogenesis of these proteins, the haem cofactor is typically incorporated enzymatically into the haem pockets of the apo-haemprotein as the functionally indispensable prosthetic g...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature02003
更新日期:2003-10-02 00:00:00
abstract::The growth of blood vessels (a process known as angiogenesis) is essential for organ growth and repair. An imbalance in this process contributes to numerous malignant, inflammatory, ischaemic, infectious and immune disorders. Recently, the first anti-angiogenic agents have been approved for the treatment of cancer and...
journal_title:Nature
pub_type: 杂志文章,评审
doi:10.1038/nature04478
更新日期:2005-12-15 00:00:00
abstract::Water striders Gerridae are insects of characteristic length 1 cm and weight 10 dynes that reside on the surface of ponds, rivers, and the open ocean. Their weight is supported by the surface tension force generated by curvature of the free surface, and they propel themselves by driving their central pair of hydrophob...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature01793
更新日期:2003-08-07 00:00:00
abstract::How diverse cell fates and complex forms emerge and feed back to each other to sculpt functional organs remains unclear. In the developing heart, the myocardium transitions from a simple epithelium to an intricate tissue that consists of distinct layers: the outer compact and inner trabecular layers. Defects in this p...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-2946-9
更新日期:2020-12-01 00:00:00
abstract::ATP, the principal energy currency of the cell, fuels most biosynthetic reactions in the cytoplasm by its hydrolysis into ADP and inorganic phosphate. Because resynthesis of ATP occurs in the mitochondrial matrix, ATP is exported into the cytoplasm while ADP is imported into the matrix. The exchange is accomplished by...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature02056
更新日期:2003-11-06 00:00:00
abstract::Cells sense the context in which they grow to adapt their phenotype and allow multicellular patterning by mechanisms of autocrine and paracrine signalling. However, patterns also form in cell populations exposed to the same signalling molecules and substratum, which often correlate with specific features of the popula...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature14429
更新日期:2015-07-02 00:00:00
abstract::When an intense laser pulse is focused into a gas, the light-atom interaction that occurs as atoms are ionized results in an extremely nonlinear optical process--the generation of high harmonics of the driving laser frequency. Harmonics that extend up to orders of about 300 have been reported, some corresponding to ph...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35018029
更新日期:2000-07-13 00:00:00
abstract::There seems a real prospect that one of the infectious scourges of the past half century will not persist much beyond the present century, but polio will be only the second infection of human beings to be eradicated. Many more remain. ...
journal_title:Nature
pub_type: 社论
doi:10.1038/374663a0
更新日期:1995-04-20 00:00:00
abstract::Developing neurons transiently express somatostatin and its receptors, but little is known about their function at these early stages. As we thought that endogenous somatostatin might control the migratory behaviour of immature neurons, we have examined the effects of somatostatin in cerebellar granule cells of early ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/415077a
更新日期:2002-01-03 00:00:00
abstract::Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis o...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature08734
更新日期:2010-02-04 00:00:00
abstract::In this Letter, 'released' should have been 'regulated' in the sentence starting: 'Deletion of Atg5 in the host similarly regulated circulating arginine and suppressed tumorigenesis...' This has been corrected online. ...
journal_title:Nature
pub_type: 杂志文章,已发布勘误
doi:10.1038/s41586-018-0815-6
更新日期:2019-01-01 00:00:00
abstract::Activity-dependent change in the efficacy of transmission is a basic feature of many excitatory synapses in the central nervous system. The best understood postsynaptic modification involves a change in responsiveness of AMPAR (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor)-mediated currents follo...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35013064
更新日期:2000-05-25 00:00:00
abstract::Enhancers are DNA sequences that stimulate transcription from eukaryotic promoters. This stimulatory effect can be exerted over large distances and from a position either 5' or 3' of a promoter. Enhancers have been found in the genomes of many viruses, and in some cellular genes such as those encoding immunoglobulin h...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/322383a0
更新日期:1986-07-24 00:00:00
abstract::Obesity is now so common within the world's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. In particular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing disorders. O...
journal_title:Nature
pub_type: 杂志文章,评审
doi:10.1038/35007508
更新日期:2000-04-06 00:00:00
abstract::Temperature-dependent transition of conductance in ionic channels has been described in several membrane systems. We report here an abrupt change in the maximal rate of rise of the action potentials of the rat extensor digitorum longus (EDL) at 32 degrees C, indicating alteration in the functional characteristics of t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/283485a0
更新日期:1980-01-31 00:00:00
abstract::Herpesviruses are characterized by their ability to maintain life-long latent infections in their animal hosts. However, the mechanisms that allow establishment and maintenance of the latent state remain poorly understood. Herpes simplex virus 1 (HSV-1) establishes latency in neurons of sensory ganglia, where the only...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature07103
更新日期:2008-08-07 00:00:00