West, R.J.H. orcid.org/0000-0001-9873-2258, Ugbode, C., Gao, F.-B. et al. (1 more author) (2018) The pro-apoptotic JNK scaffold POSH/SH3RF1 mediates CHMP2BIntron5-associated toxicity in animal models of frontotemporal dementia. Human Molecular Genetics, 27 (8). pp. 1382-1395. ISSN 0964-6906
Abstract
Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. However, the pathological mechanisms driving neuronal atrophy in FTD remain poorly understood. Here we identify a conserved role for the novel pro-apoptotic protein plenty of SH3s (POSH)/SH3 domain containing ring finger 1 in mediating neuropathology in Drosophila and mammalian models of charged multivesicular body protein 2B (CHMP2BIntron5) associated FTD. Aberrant, AKT dependent, accumulation of POSH was observed throughout the nervous system of both Drosophila and mice expressing CHMP2BIntron5. Knockdown of POSH was shown to be neuroprotective and sufficient to alleviate aberrant neuronal morphology, behavioral deficits and premature-lethality in Drosophila models, as well as dendritic collapse and cell death in CHMP2BIntron5expressing rat primary neurons. POSH knockdown also ameliorated elevated markers of Jun N-terminal kinase and apoptotic cascades in both Drosophila and mammalian models. This study provides the first characterization of POSH as a potential component of an FTD neuropathology, identifying a novel apoptotic pathway with relevance to the FTD spectrum.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License. (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 16 Jun 2022 10:15 |
Last Modified: | 18 Jun 2022 00:54 |
Status: | Published |
Publisher: | Oxford University Press (OUP) |
Refereed: | Yes |
Identification Number: | 10.1093/hmg/ddy048 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:188077 |