A novel synaptopathy‐defective synaptic vesicle protein trafficking in the mutant CHMP2B mouse model of frontotemporal dementia. Issue 3 (11th December 2021)

• Record Type: Journal Article
• Authors: Clayton, Emma L.; Bonnycastle, Katherine; Isaacs, Adrian M.; Cousin, Michael A.; Schorge, Stephanie
• Is Part Of: Journal of neurochemistry. Volume 160:Issue 3(2022)
• Page Start: 412
• Page End: 425
• Publication Date: 2021-12-11
• Subjects: CHMP2B -- endosome -- ESCRT -- frontotemporal dementia -- lysosome -- synaptic vesicle; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15551
• Languages: English
• ISSNs: 0022-3042

Abstract

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. Abstract : Mutation in charged multivesicular body protein 2B (CHMP2B) causes frontotemporal dementia and leads to impaired endolysosomal trafficking and lysosomal storage pathology in neurons. Western blotting shows select synaptic vesicle proteins are retained in aged transgenic CHMP2B mice despite significant loss of postsynaptic proteins. Ultrastructural analysis of primary cortical cultures from transgenic CHMP2B mice reveals a significant increase in presynaptic endosome number, while neurons expressing mutant CHMP2B display defective synaptic vesicle recycling and alterations to functional synaptic vesicle pools. We show here how mutations in CHMP2B affect levels of specific presynaptic proteins and synaptic vesicle recycling, identifying CHMP2B frontotemporal dementia as a novel synaptopathy.