Mechanisms of disease articles within Nature

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  • Article |

    Stabilization of a transient protein kinase–substrate complex using a nanobody provides molecular details about how the Parkinson’s disease-linked protein kinase PINK1 phosphorylates ubiquitin, and suggests new pharmacological strategies.

    • Alexander F. Schubert
    • , Christina Gladkova
    •  & David Komander

  • Letter |

    The growth of adult and paediatric brain tumours depends on a microenvironmental signalling pathway involving the activity-regulated secretion of neuroligin-3 (NLGN3) from normal neurons and oligodendrocyte precursor cells, highlighting the potential of NLGN3 as a therapeutic target.

    • Humsa S. Venkatesh
    • , Lydia T. Tam
    •  & Michelle Monje

  • Letter |

    The polyglutamine domain in ataxin 3, which is expanded in spinocerebellar ataxia type 3, allows normal ataxin 3 to interact with and deubiquitinate beclin 1 and thereby to promote autophagy.

    • Avraham Ashkenazi
    • , Carla F. Bento
    •  & David C. Rubinsztein

  • Article |

    Osteoblast-derived LCN2 activates the melanocortin 4 receptor in neurons of the paraventricular nucleus of the hypothalamus to suppress appetite, regulates insulin secretion and increases insulin sensitivity and glucose tolerance.

    • Ioanna Mosialou
    • , Steven Shikhel
    •  & Stavroula Kousteni

  • Letter |

    Two related papers show that cells disseminated from malignant lesions at early time points during tumorigenesis can contribute to metastases at distant organs and provide insights into the molecular basis of dissemination.

    • Kathryn L. Harper
    • , Maria Soledad Sosa
    •  & Julio A. Aguirre-Ghiso

  • Letter |

    Atherosclerotic lesions in mice and humans switch on a ‘don’t eat me’ signal—expression of CD47—that prevents effective removal of diseased tissue; anti-CD47 antibody therapy can normalize this defective efferocytosis, with beneficial results in several mouse models of atherosclerosis.

    • Yoko Kojima
    • , Jens-Peter Volkmer
    •  & Nicholas J. Leeper

  • Letter |

    PGC1α protects against kidney injury by upregulating enzymes that enhance nicotinamide adenine dinucleotide (NAD) and driving local accumulation of the fatty acid breakdown product β-hydroxybutyrate, which leads to increased production of the renoprotective prostaglandin E2.

    • Mei T. Tran
    • , Zsuzsanna K. Zsengeller
    •  & Samir M. Parikh

  • Letter |

    A mechanism for phosphoinositide conversion at endosomes to enable exit from the endosomal system, suggesting that defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy.

    • Katharina Ketel
    • , Michael Krauss
    •  & Volker Haucke

  • Article |

    A new deep proteomic analysis method is used to identify proteins that interact with wild-type cystic fibrosis transmembrane conductance regulator (CFTR) and its mutant version that is the major cause of cystic fibrosis.

    • Sandra Pankow
    • , Casimir Bamberger
    •  & John R. Yates III

  • Article |

    Exosomes originating from lung-, liver- and brain-tropic tumour cells are preferentially incorporated by specific resident cells of the target organs, thus preparing the site for metastasis; the expression of distinct combinations of exosomal integrin proteins determines the exosomal targeting to each of the three organs, and blocking these integrins reduces organotropic exosome uptake by the target organs, thereby reducing the likelihood of organotropic metastasis.

    • Ayuko Hoshino
    • , Bruno Costa-Silva
    •  & David Lyden

  • Letter |

    Exploring the genetic basis of congenital cataracts in two families identifies a molecule, lanosterol, which prevents intracellular protein aggregation of various cataract-causing mutant crystallins, and which can reduce cataract severity and increase lens transparency in vivo in dogs.

    • Ling Zhao
    • , Xiang-Jun Chen
    •  & Kang Zhang

  • Letter |

    Studies in mice reveal that CREB regulated transcription coactivator 2 (CRTC2) acts as a mediator of mTOR signalling in the liver to regulate SREBP1-controlled lipid homeostasis during feeding and diabetes; overexpression of a CRTC2 mutant defective for mTOR regulation improves the lipogenic program and insulin sensitivity in obese mice.

    • Jinbo Han
    • , Erwei Li
    •  & Yiguo Wang

  • Letter |

    Artemisinins are key anti-malarial drugs, but artemisinin resistance has been increasing; this study identifies the molecular target of artemisinins as phosphatidylinositol-3-kinase and increase of the lipid product phosphatidylinositol-3-phosphate induces resistance in Plasmodium falciparum.

    • Alassane Mbengue
    • , Souvik Bhattacharjee
    •  & Kasturi Haldar

  • Letter |

    Here, DNA damage is shown to occur as a direct consequence of inducing haematopoietic stem cells to exit quiescence in response to conditions of stress; in mice with mutations modelling those seen in Fanconi anaemia, this leads to a complete collapse of the haematopoietic system.

    • Dagmar Walter
    • , Amelie Lier
    •  & Michael D. Milsom

  • Article |

    This study reports the correction of pulmonary alveolar proteinosis (PAP) in Csf2rb–/– mice by a single transfer of either wild-type or gene-corrected macrophages directly to the lungs — the transplanted macrophages persisted for at least 1 year; this transplantation strategy obviated the need for myeloablation and immunosuppression and should be a feasible therapy for humans with hereditary PAP.

    • Takuji Suzuki
    • , Paritha Arumugam
    •  & Bruce C. Trapnell

  • Letter |

    Ubiquitin, known for its role in post-translational modification of other proteins, undergoes post-translational modification itself; after a decrease in mitochondrial membrane potential, the kinase enzyme PINK1 phosphorylates ubiquitin at Ser 65, and the phosphorylated ubiquitin then interacts with ubiquitin ligase (E3) enzyme parkin, which is also phosphorylated by PINK1, and this process is sufficient for full activation of parkin enzymatic activity.

    • Fumika Koyano
    • , Kei Okatsu
    •  & Noriyuki Matsuda

  • Letter |

    Nicotinamide N-methyltransferase (NNMT) expression is increased in white adipose tissue and liver of obese and diabetic mice, Nnmt knockdown protects against diet-induced obesity by altering the availability of adipose S-adenosylmethionine and NAD+, rendering Nnmt a novel target for treating obesity and type 2 diabetes.

    • Daniel Kraus
    • , Qin Yang
    •  & Barbara B. Kahn

  • Article |

    Structurally polymorphic C9orf72 hexanucleotide repeats cause an impairment in transcriptional processivity and lead to accumulation of truncated repeat-containing transcripts that bind to specific ribonucleoproteins, such as nucleolin, in a conformation-dependent manner resulting in nucleolar stress and C9orf72-linked pathology in amyotrophic lateral sclerosis and frontotemporal dementia.

    • Aaron R. Haeusler
    • , Christopher J. Donnelly
    •  & Jiou Wang

  • Article |

    An orally active small molecule, AdipRon, that binds to and activates both adiponectin receptors (AdipoR1 and AdipoR2) is identified; it ameliorates diabetes in mice on a high-fat diet and in genetically obese db/db mice, and if this can be extrapolated to humans, orally active agonists such as AdipoRon are a promising new approach to treat obesity-related diseases such as type 2 diabetes.

    • Miki Okada-Iwabu
    • , Toshimasa Yamauchi
    •  & Takashi Kadowaki

  • Letter |

    This study finds a direct correlation between LARGE-glycan extension on dystroglycan and the protein’s capacity for extracellular matrix ligands; in regenerating mouse muscle, short LARGE-glycan polysaccharides cause various defects, including muscle dysfunction and a predisposition to dystrophy, and in muscular dystrophy patients, increased clinical severity of disease corresponds to shorter LARGE-glycans.

    • Matthew M. Goddeeris
    • , Biming Wu
    •  & Kevin P. Campbell

  • Letter |

    Cerebral cavernous malformations associated with loss of function of Ccm1 are shown to be formed by endothelial cells undergoing endothelial-to-mesenchymal transition (EndMT) induced by TGF-β and BMP signalling; inhibition of TGF-β and BMP signalling prevents EndMT and the appearance of CCM lesions.

    • Luigi Maddaluno
    • , Noemi Rudini
    •  & Elisabetta Dejana

  • Letter |

    Lamin and emerin mutations causing cardiomyopathies are associated with an impairment in actin dynamics, resulting in aberrant nuclear translocation and downstream signalling of the transcription factor MKL1, which is pivotal for cardiac development.

    • Chin Yee Ho
    • , Diana E. Jaalouk
    •  & Jan Lammerding

  • Article |

    The identification of pathogenic mutations within prion-like domains (PrLDs) of the RNA-binding proteins hnRNPA2B1 and hnRNPA1 add to our understanding of how mutations in these proteins lead to degenerative disease, and highlight the potential importance of PrLDs in degenerative diseases of the nervous system, muscle and bone.

    • Hong Joo Kim
    • , Nam Chul Kim
    •  & J. Paul Taylor

  • Letter |

    A new mechanism of chromosomal rearrangement is identified through the observation that broken or collapsed DNA replication forks restarted by homologous recombination have a high propensity for U-turns at short inverted repeats; the error-prone nature of this mechanism is suggested to contribute to gross chromosomal rearrangements and copy-number variations present in cancer and other genomic disorders.

    • Ken’Ichi Mizuno
    • , Izumi Miyabe
    •  & Johanne M. Murray

  • Article |

    Heat stroke triggers necrotic cell death and neurodegeneration in Caenorhabditis elegans, but hormetic preconditioning at a mildly elevated temperature strongly protects C. elegans from necrosis induced by several insults, including heat, and shields mammalian neurons from heat cytotoxicity, suggesting that this protective mechanism is conserved.

    • Nikos Kourtis
    • , Vassiliki Nikoletopoulou
    •  & Nektarios Tavernarakis

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