Neurological disorders

  • Article |

    The authors report the structures of glutamate-gated kainate receptors in complex with NETO2 in both the resting and the desensitized states and reveal how kainate receptors in the brain are regulated by NETO2.

    • Lingli He
    • , Jiahui Sun
    •  & Yan Zhao
  • Article |

    A protein chaperone system is identified that consists of proteins with poly-Asp/Glu sequence, and may have an important role in diseases characterized by protein aggregation.

    • Liangqian Huang
    • , Trisha Agrawal
    •  & Xiaolu Yang
  • Article |

    Aggressive cerebral cavernous malformations (CCMs) are found to grow through a three-hit cancer-like mechanism, involving gain of function of a gene that promotes vascular growth, and loss of function of genes that suppress it.

    • Aileen A. Ren
    • , Daniel A. Snellings
    •  & Mark L. Kahn
  • Article |

    Genome-wide analysis of tandem DNA repeats in the genomes of individuals with autism spectrum disorder and control participants reveals a strong contribution of tandem repeat expansions to the genetic aetiology and phenotypic complexity of autism spectrum disorder.

    • Brett Trost
    • , Worrawat Engchuan
    •  & Ryan K. C. Yuen
  • Article |

    The lysosomal polyamine transporter ATP13A2 controls the cellular polyamine content, and impaired lysosomal polyamine export represents a lysosome-dependent cell death pathway that may be implicated in ATP13A2-associated neurodegeneration.

    • Sarah van Veen
    • , Shaun Martin
    •  & Peter Vangheluwe
  • Article |

    The authors show that NLRP3 inflammasome is activated in microglia of patients with fronto-temporal dementia and in a mouse model of tau pathology, and that the loss of NLRP3 inflammasome function decreases tau pathology and improves cognition in mice.

    • Christina Ising
    • , Carmen Venegas
    •  & Michael T. Heneka
  • Article |

    Activated clonally expanded CD4+ T cells display specificity to the myelin peptide MOG, whereas clonally expanded CD8+ T cells depend on T cell receptor recognition of unrelated surrogate peptides and have a regulatory function.

    • Naresha Saligrama
    • , Fan Zhao
    •  & Mark M. Davis
  • Letter |

    Single-nucleus RNA sequencing analysis identifies different subclusters of oligodendroglia in white matter from individuals with multiple sclerosis compared with controls, and these differences may be important for understanding disease progression.

    • Sarah Jäkel
    • , Eneritz Agirre
    •  & Gonçalo Castelo-Branco
  • Article |

    Cytoplasmic, amyloid-like oligomeric assemblies that contain TDP-43 are increased in damaged tissues with elevated regeneration, thereby enhancing the possibility of amyloid fibre formation and/or aggregation of TDP-43 in disease.

    • Thomas O. Vogler
    • , Joshua R. Wheeler
    •  & Roy Parker
  • Letter |

    A genome-wide association study of approximately 7,000 patients with neurodevelopmental disorders demonstrates that overall risk and clinical presentation in putative monogenic disorders is also influenced by common genetic variants present in the general population.

    • Mari E. K. Niemi
    • , Hilary C. Martin
    •  & Jeffrey C. Barrett
  • Letter |

    The structure of huntingtin in complex with an interactor is determined to an overall resolution of 4 Å, paving the way for improved understanding of the cellular functions of this protein.

    • Qiang Guo
    • , Bin Huang
    •  & Stefan Kochanek
  • Letter |

    Experimental evidence that global Kctd13 reduction leads to increased RhoA levels that reduce synaptic transmission, implicating RhoA as a potential therapeutic target for neuropsychiatric disorders associated with copy-number variants that include KCTD13.

    • Christine Ochoa Escamilla
    • , Irina Filonova
    •  & Craig M. Powell
  • 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 |

    Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.

    • Jeremy F. McRae
    • , Stephen Clayton
    •  & Matthew E. Hurles
  • Letter |

    Structural differences in 40- and 42-residue-long amyloid-β fibrils seeded in vitro from the cortical tissue of patients with different clinical subtypes of Alzheimer’s disease suggest that different fibril structures form in different disease variants and with different peptide lengths.

    • Wei Qiang
    • , Wai-Ming Yau
    •  & Robert Tycko
  • Article |

    Aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ, reduces soluble and insoluble Aβ in the brain, an action accompanied by a dose-dependent slowing of clinical decline in treated patients.

    • Jeff Sevigny
    • , Ping Chiao
    •  & Alfred Sandrock
  • Letter |

    A human neurodevelopmental model fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

    • Thanathom Chailangkarn
    • , Cleber A. Trujillo
    •  & Alysson R. Muotri
  • Brief Communications Arising |

    • John Collinge
    • , Zane Jaunmuktane
    •  & Sebastian Brandner
  • Article |

    Sustained delivery of axon-specific growth factors not typically present in spinal cord lesions allows for robust axonal regrowth only if the astrocytic scar is present—a result that questions the prevailing dogma and suggests that astrocytic scarring aids rather than prevents central nervous system axon regeneration post injury.

    • Mark A. Anderson
    • , Joshua E. Burda
    •  & Michael V. Sofroniew
  • Letter |

    Deep brain stimulation (DBS) of the fimbria–fornix—a region that provides input to the hippocampus—is shown to restore hippocampus-dependent memory and hippocampal long-term potentiation and neurogenesis in a mouse model of Rett syndrome, suggesting that DBS, which is already used in the treatment of several neurological conditions, could be a viable approach to mitigating cognitive impairment in Rett syndrome and other disorders of childhood intellectual disability.

    • Shuang Hao
    • , Bin Tang
    •  & Jianrong Tang
  • Letter |

    Treatment of children with human cadaver-derived growth hormone (c-hGH) contaminated with prions resulted in transmission of Creutzfeldt–Jakob disease (CJD); unexpectedly, in an autopsy study of eight such iCJD patients, the authors found amyloid-β deposition in the grey matter typical of that seen in Alzheimer's disease and amyloid-β in the blood vessel walls characteristic of cerebral amyloid angiopathy, consistent with iatrogenic transmission of amyloid-β pathology in addition to CJD and suggests that healthy c-hGH-exposed individuals may also be at risk of Alzheimer's disease and cerebral amyloid angiopathy.

    • Zane Jaunmuktane
    • , Simon Mead
    •  & Sebastian Brandner
  • Letter |

    An unbiased genetic screen in Drosophila expressing G4C2-repeat-containing transcripts (repeats that in human cause pathogenesis in C9orf72-related neurological disease) finds genes that encode components of the nuclear pore and nucleocytoplasmic transport machinery, and reveals that G4C2 expanded-repeat-induced alterations in nucleocytoplasmic transport contribute to C9orf72 pathology and neurodegeneration.

    • Brian D. Freibaum
    • , Yubing Lu
    •  & J. Paul Taylor
  • Letter |

    Whole-exome sequencing reveals that a rare variant of phospholipase D3 (PLD3(V232M)) segregates with Alzheimer’s disease status in two independent families and doubles risk for the disease in case–control series, and that several other PLD3 variants increase risk for Alzheimer’s disease in African Americans and people of European descent.

    • Carlos Cruchaga
    • , Celeste M. Karch
    •  & Alison M. Goate
  • Article |

    This study reports a global analysis of binding sites for over 200 RNA-binding proteins (RBPs) from 24 species; conserved RNA-binding motifs are identified, and their analysis allows prediction of interaction sites based on the sequence of the RNA-binding domain alone.

    • Debashish Ray
    • , Hilal Kazan
    •  & Timothy R. Hughes
  • Article |

    Presenilin, the catalytic component of γ-secretase, cleaves amyloid precursor protein into short peptides that form the plaques that are found in the brains of patients with Alzheimer’s disease; here the structure of a presenilin homologue is described, which will serve as a framework for understanding the mechanisms of action of presenilin and γ-secretase.

    • Xiaochun Li
    • , Shangyu Dang
    •  & Yigong Shi