Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy
Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1-121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50-57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.
Publication date: Available online 27 January 2020Source: The Lancet NeurologyAuthor(s): Franziska Hopfner, Günter U Höglinger, Gregor Kuhlenbäumer, Anton Pottegård, Mette Wod, Kaare Christensen, Caroline M Tanner, Günther DeuschlSummaryBackgroundβ-adrenoceptors are widely expressed in different human organs, mediate important body functions and are targeted by medications for various diseases (such as coronary heart disease and heart attack) and many β-adrenoceptor acting drugs are listed on the WHO Model List of Essential Medicines. β-adrenoceptor antagonists are used by billions ...
We present a neurobiologically plausible elaboration of an existing schema-based cognitive model of action selection in which the basal ganglia implements an activation-based selection process that mediates between assumed cortical representations of rule-based schemas. More specifically, the model employs a network of basal ganglia units with computations performed by individual BG nuclei, embedded in a corticothalamic loop that disinhibits schemas according to the received feedback. We provide bridging assumptions for linking the operation of the model with ERP components that describe the error-related negativity (ERN) ...
Condition: Parkinson Disease Interventions: Other: 11C-UCB-J PET-CT; Other: 18F-PE2I PET-MR Sponsor: Universitaire Ziekenhuizen Leuven Recruiting
PARKINSON'S disease is a progressive nervous system disorder that affects movement. An obvious early sign of the disease is uncontrolled movements. Less obvious signs of the condition can appear when a person sleeps. What are they?
This study was registered with the Chinese Clinical Trial Registry under ChiCTR-TRC-14004707. Registered on May 27, 2014.
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