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

• Published in: Human molecular genetics 2018-04, Vol.27 (8), p.1382-1395
• Main Authors: West, Ryan J H, Ugbode, Chris, Gao, Fen-Biao, Sweeney, Sean T
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Apoptosis - genetics; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cytoskeletal Proteins - antagonists & inhibitors; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Disease Models, Animal; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - antagonists & inhibitors; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Frontotemporal Dementia - pathology; Gene Expression Regulation; Humans; Introns; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; Larva - genetics; Larva - metabolism; Longevity - genetics; Mice; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nervous System - metabolism; Nervous System - pathology; Neurons - metabolism; Neurons - pathology; Primary Cell Culture; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rats; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism
• ISSN: 0964-6906; 1460-2083; 1460-2083
• 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.