A novel synaptopathy-defective synaptic vesicle protein trafficking in the mutant CHMP2B mouse model of frontotemporal dementia.

Emma L Clayton,Stephanie Schorge,Adrian M Isaacs,Katherine Bonnycastle,Michael A Cousin

doi:10.1111/jnc.15551

Abstract

Mutations in the ESCRT-III subunit CHMP2B cause frontotemporal dementia (FTD) and lead to impaired endolysosomal trafficking and lysosomal storage pathology in neurons. We investigated the effect of mutant CHMP2B on synaptic pathology, as ESCRT function was recently implicated in the degradation of synaptic vesicle (SV) proteins. We report here that expression of C-terminally truncated mutant CHMP2B results in a novel synaptopathy. This unique synaptic pathology is characterised by selective retention of presynaptic SV trafficking proteins in aged mutant CHMP2B transgenic mice, despite significant loss of postsynaptic proteins. Furthermore, ultrastructural analysis of primary cortical cultures from transgenic CHMP2B mice revealed a significant increase in the number of presynaptic endosomes, while neurons expressing mutant CHMP2B display defective SV recycling and alterations to functional SV pools. Therefore, we reveal how mutations in CHMP2B affect specific presynaptic proteins and SV recycling, identifying CHMP2B FTD as a novel synaptopathy. This novel synaptopathic mechanism of impaired SV physiology may be a key early event in multiple forms of FTD, since proteins that mediate the most common genetic forms of FTD all localise at the presynapse.

Highlights

Synaptopathies are disorders resulting from dysfunction of synapses and are associated with the earliest stages of multiple neuronal diseases
Mutations in the genes that encode tau (MAPT), progranulin (GRN) and C9orf72 are the most common, while additional rare mutations have been identified in valosin-containing protein (VCP), TDP-43 (TARDBP), fused in sarcoma (FUS) (Rohrer & Warren, 2011), TANK-binding kinase 1 (TBK1) (Gijselinck et al, 2015; Le Ber et al, 2015; Pottier et al, 2015; van der Zee et al, 2017) and charged multivesicular body protein 2B (CHMP2B) (Lindquist et al, 2008; Skibinski et al, 2005)
Since nerve terminal stimulation dynamically alters the proportion of synaptic vesicle (SV) and endosomes in the short term, we examined the effects of stimulation on the presynaptic ultrastructure

Summary

| INTRODUCTION

Synaptopathies are disorders resulting from dysfunction of synapses and are associated with the earliest stages of multiple neuronal diseases. In frontotemporal dementia (FTD) patients have lower synaptic density in the superficial layers of the frontal cortex (Ferrer, 1999; Liu et al, 1996) It is not clear what is causing the damage to synapses in FTD, nor how this damage contributes to the clinical outcome for the disorder. The mutation disrupts a splice acceptor site and generates a C-terminally truncated variant of the protein Physiological levels of this mutant CHMP2B are sufficient to recapitulate the patient phenotype in mice, producing axonal degeneration, gliosis and progressive neurodegeneration (Clayton et al, 2015, 2017; Gascon et al, 2014; Ghazi-Noori et al, 2012). We report here that defects in SV protein physiology caused by mutant CHMP2B affect presynaptic SV trafficking, leading to synaptopathy in CHMP2B FTD

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION