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Publication Detail
The modulation of tau proteostasis in tauopathies by NUB1/NUB1L interaction with the autophagy-lysosomal pathway
  • Publication Type:
    Thesis/Dissertation
  • Authors:
    Guarascio R
  • Date awarded:
    2019
  • Pagination:
    2, 263
  • Awarding institution:
    UCL (University College London)
  • Language:
    English
Abstract
NEDD8 ultimate buster 1 (NUB1) and its longer isoform NUB1L are ubiquitin-like (UBL)/ ubiquitin-associated (UBA) proteins that target the downregulation of ubiquitin-like modifiers and aggregation-prone proteins leading to neurodegeneration (synphilin-1, huntingtin and tau). Previous data revealed that the NUB1-mediated reduction in tau phosphorylation and aggregation was enhanced upon proteasome inhibition, suggesting a switch in NUB1 function from targeted proteasomal degradation to a role in autophagy. The aim of this study was to test this hypothesis and understand the molecular mechanisms involved. NUB1 expression and localization was localized in the hippocampus of transgenic mice models of tauopathy. In wild type animals, NUB1 localized to the nuclei of neurons but also co-localized with tau along neuronal axons. In pathological models at later stages, NUB1 localized in cytosolic inclusions positive for pathological forms of tau and components of the autophagy-lysosomal machinery (p62 and LAMP1). From 12 months, NUB1 expression decreased in animal models with a severe pathology. To investigate the role of NUB1 in vitro, a GFP-tau inducible neuroblastoma cell line was generated and treated with proteasome inhibitor to induce the formation of aggresomes. NUB1 significantly decreased the ratio of phosphorylated tau to tau, particularly following proteasomal inhibition. Moreover, analysis of phosphorylated tau fractionating to the detergent insoluble fraction revealed that NUB1 targets aggregation-prone phosphorylated tau. Interestingly, upon proteasome inhibition, NUB1/NUB1L increased the levels of the autophagosome marker LC3BII and increased the size and numbers of LC3B puncta. Moreover, NUB1 increased the recruitment of LAMP1 positive vesicles around the aggresomes and interacted with p62 in a manner dependent on proteasome inhibition. Autophagy flux assays revealed that NUB1/NUB1L blocked the autophagy-lysosomal pathway downstream of autophagosome formation. Assays conducted with NUB1L lacking the UBA or UBL domain revealed that while both these domains were required for the block in autophagy, the UBA domain was primarily involved in this function. Accordingly, the increase in the level of autophagosomes and interaction with p62 upon proteasome inhibition was compromised by deletion of the UBA domain.
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