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The Pro-Apoptotic JNK Scaffold POSH/SH3RF1 Mediates CHMP2BIntron5-Associated Toxicity in Animal Models Frontotemporal Dementia

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JournalHuman Molecular Genetics
DateAccepted/In press - 5 Feb 2018
DateE-pub ahead of print - 8 Feb 2018
DatePublished (current) - 15 Apr 2018
Issue number8
Volume27
Number of pages14
Pages (from-to)1382–1395
Early online date8/02/18
Original languageEnglish

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 POSH/SH3RF1 in mediating neuropathology in Drosophila and mammalian models of 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 CHMP2BIntron5 expressing rat primary neurons. POSH knockdown also ameliorated elevated markers of JNK 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.

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© The Author 2018.

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