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Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes
Woo JA, Liu T, Zhao X, Trotter C, Yrigoin K, Cazzaro S, Narvaez E, Khan H et al.. Human molecular genetics, 2017-10-01
Topic: Brain proteins, microglia and lab models
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.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Woo, J. A., Liu, T., Zhao, X., Trotter, C., Yrigoin, K., Cazzaro, S., et al. (2017). Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes. Human molecular genetics. https://doi.org/10.1093/hmg/ddx284
Vancouver
Woo JA, Liu T, Zhao X, Trotter C, Yrigoin K, Cazzaro S, et al. Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes. Human molecular genetics. 2017. doi:10.1093/hmg/ddx284. PMID: 29016855.
BibTeX
@article{woo2017-29016855,
author = {Woo, J. A. and Liu, T. and Zhao, X. and Trotter, C. and Yrigoin, K. and Cazzaro, S. and Narvaez, E. and Khan, H. and others},
title = {{Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes}},
journal = {Human molecular genetics},
year = {2017},
doi = {10.1093/hmg/ddx284},
pmid = {29016855},
url = {https://doi.org/10.1093/hmg/ddx284}
}
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Key findings
- 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.
- 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).
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Study details
- Evidence strengthLow
How this study scored 38/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 22 of the 58 points we could judge it on, which is 38 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Human molecular genetics) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2017 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 29016855) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 22 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 22 of the 58 points we could judge it on is 38 out of 100. |
| Total | 38 / 100 | — |
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