Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes
| Autor: | Ksenia Yrigoin, Courtney Trotter, Richard Witas, Sara Cazzaro, David E. Kang, Chad A. Dickey, Kamal Makati, Anusha Bukhari, Emilio De Narvaez, Xingyu Zhao, Tian Liu, Xinming Wang, Jung A. Woo, Hirah Khan |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Scaffold protein Mice Transgenic tau Proteins Hippocampus Mice 03 medical and health sciences Alzheimer Disease Heat shock protein Genetics medicine Animals Humans HSP90 Heat-Shock Proteins Molecular Biology Cells Cultured Genetics (clinical) Adaptor Proteins Signal Transducing Neurons Gene knockdown Amyloid beta-Peptides biology HSC70 Heat-Shock Proteins Neurotoxicity Brain Nuclear Proteins Signal transducing adaptor protein Articles General Medicine medicine.disease Hsp90 Cell biology Mice Inbred C57BL Cytoskeletal Proteins 030104 developmental biology Tauopathies Chaperone (protein) biology.protein Tauopathy HeLa Cells |
| Zdroj: | Human Molecular Genetics. 26:3973-3988 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddx284 |
| Popis: | Accumulation of amyloid β (Aβ) and tau represent the two major pathological hallmarks of Alzheimer’s disease (AD). Despite the critical importance of Aβ accumulation as an early event in AD pathogenesis, multiple lines of evidence indicate that tau is required to mediate Aβ-induced neurotoxic signals in neurons. We have previously shown that the scaffolding protein Ran-binding protein 9 (RanBP9), which is highly elevated in brains of AD and AD mouse models, both enhances Aβ production and mediates Aβ-induced neurotoxicity. However, it is unknown whether and how RanBP9 transmits Aβ-induced neurotoxic signals to tau. Here we show for the first time that overexpression or knockdown of RanBP9 directly enhances and reduces tau levels, respectively, in vitro and in vivo. Such changes in tau levels are associated with the ability of RanBP9 to physically interact with tau and heat shock protein 90/heat shock cognate 70 (Hsp90/Hsc70) complexes. Meanwhile, both RanBP9 and tau levels are simultaneously reduced by Hsp90 or Hsc70 inhibitors, whereas overexpression or knockdown of RanBP9 significantly diminishes the anti-tau potency of Hsp90/Hsc70 inhibitors as well as Hsc70 variants (WT & E175S). Further, RanBP9 increases the capacity for Hsp90 and Hsc70 complexes to bind ATP and enhances their ATPase activities in vitro. These observations in vitro and cell lines are recapitulated in primary neurons and in vivo, as genetic reduction in RanBP9 not only ameliorates tauopathy in Tau-P301S mice but also rescues the deficits in synaptic integrity and plasticity. |
| Databáze: | OpenAIRE |
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