A POSH accent for synaptic growth

Defects in endosomal trafficking that result in neurodegeneration stimulate synaptic growth, West et al. reveal.

Mutations in the gene encoding the ESCRT-III subunit CHMP2B have been linked to both frontotemporal dementia and amyotrophic lateral sclerosis. The ESCRT-III complex regulates the formation of endosomal multivesicular bodies, and disruptions to this process affect numerous trafficking and signaling pathways. To investigate which of these pathways contribute to neurodegeneration, West et al. screened for mutations that enhance the death of Drosophila eye cells expressing a disease-associated dominant mutant version of CHMP2B.

Mutations in the gene encoding the small GTPase Rab8 enhanced mutant CHMP2B-induced cell death, the researchers found. Motor neurons lacking Rab8 function formed extra-large synapses with muscle cells due to an increase in JNK and TGF-β signaling. Rab8 localized to recycling endosomes, and markers for these organelles were reduced in Rab8 mutant flies. Additionally, a protein called POSH accumulated on late endosomes. POSH scaffolds an upstream activator of the JNK pathway called TAK1 and is also an E3 ubiquitin ligase that promotes the destruction of the TGF-β regulator HRS. Removing POSH from Rab8 mutant flies reduced the activity of both signaling pathways and restored synaptic growth to normal levels.

Dominant CHMP2B also induced POSH accumulation in mammalian neurons and synaptic overgrowth in Drosophila larvae, a phenotype suppressed by overexpressing wild-type Rab8. Thus, disruptions to multivesicular bodies or recycling endosomes cause POSH to accumulate and activate signaling pathways that stimulate synaptic growth. The same pathways could also promote neurodegeneration, so senior author Sean Sweeney now wants to identify additional genes involved in the process.