The pro-apoptotic JNK scaffold POSH/SH3RF1 mediates CHMP2BIntron5-associated toxicity in animal models of frontotemporal dementia.

Ryan J H West,Chris Ugbode,Fen-Biao Gao,Sean T Sweeney

doi:10.1093/hmg/ddy048

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.

Highlights

Frontotemporal dementia (FTD), a clinically, genetically and pathologically heterogeneous neurodegenerative disease, is a common form of early-onset dementia
We employed this model to establish whether expression of AKT could alleviate neuronal aberrations in larvae pan-neuronally [neuronal synaptobrevin-Gal4] expressing CHMP2BIntron5
Expression of CHMP2BIntron5 lead to aberrant accumulation of plenty of SH3s (POSH), which is known to be negatively regulated by AKT [18,20], in the nervous system of both Drosophila and mammalian models

Summary

Introduction

Frontotemporal dementia (FTD), a clinically, genetically and pathologically heterogeneous neurodegenerative disease, is a common form of early-onset dementia. The principal syndromes associated with FTLD include behavioral variant FTD (bvFTD), progressive nonfluent aphasia, semantic dementia and FTD with motor neuron disease (FTD-MND). We established a Drosophila model of FTD associated with the bvFTD-disease causing mutation charged multivesicular body protein 2B (CHMP2BIntron5) [7,10,11]. CHMP2BIntron causes a C-terminal truncation of the CHMP2B protein and failure of CHMP2B to dissociate from the endosomal sorting complex required for transport III complex [12,13]. Using this model we demonstrated CHMP2BIntron perturbs normal endosomal and autophagic trafficking [7,10,11]. Neuronal loss through phagocytic clearance of apoptotic neurons has been observed in CHMP2BIntron models [14], the mechanisms driving

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