eprintid: 10063313
rev_number: 23
eprint_status: archive
userid: 608
dir: disk0/10/06/33/13
datestamp: 2018-12-05 09:23:00
lastmod: 2021-10-01 23:57:43
status_changed: 2018-12-05 09:23:00
type: article
metadata_visibility: show
creators_name: Clayton, EL
creators_name: Milioto, C
creators_name: Muralidharan, B
creators_name: Norona, FE
creators_name: Edgar, JR
creators_name: Soriano, A
creators_name: Jafar-Nejad, P
creators_name: Rigo, F
creators_name: Collinge, J
creators_name: Isaacs, AM
title: Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: DF9
divisions: FA5
divisions: D07
divisions: F81
divisions: F86
keywords: frontotemporal dementia, trafficking, ESCRT, CHMP2B, TMEM106B
note: © The Author(s) 2018.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse,
distribution, and reproduction in any medium, provided the original work is properly cited.
abstract: Mutations in the endosome-associated protein CHMP2B cause frontotemporal dementia and lead to lysosomal storage pathology in neurons. We here report that physiological levels of mutant CHMP2B causes reduced numbers and significantly impaired trafficking of endolysosomes within neuronal dendrites, accompanied by increased dendritic branching. Mechanistically, this is due to the stable incorporation of mutant CHMP2B onto neuronal endolysosomes, which we show renders them unable to traffic within dendrites. This defect is due to the inability of mutant CHMP2B to recruit the ATPase VPS4, which is required for release of CHMP2B from endosomal membranes. Strikingly, both impaired trafficking and the increased dendritic branching were rescued by treatment with antisense oligonucleotides targeting the well validated frontotemporal dementia risk factor TMEM106B, which encodes an endolysosomal protein. This indicates that reducing TMEM106B levels can restore endosomal health in frontotemporal dementia. As TMEM106B is a risk factor for frontotemporal dementia caused by both C9orf72 and progranulin mutations, and antisense oligonucleotides are showing promise as therapeutics for neurodegenerative diseases, our data suggests a potential new strategy for treating the wide range of frontotemporal dementias associated with endolysosomal dysfunction.
date: 2018-12
date_type: published
official_url: https://doi.org/10.1093/brain/awy284
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article
verified: verified_manual
elements_id: 1605861
doi: 10.1093/brain/awy284
pii: 5212875
lyricists_name: Clayton, Emma
lyricists_name: Collinge, John
lyricists_name: Isaacs, Adrian
lyricists_name: Milioto, Carmelo
lyricists_name: Muralidharan, Bhavana
lyricists_id: ELCLA56
lyricists_id: JCOLL20
lyricists_id: AISAA22
lyricists_id: CMILI40
lyricists_id: BMURA64
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Brain
volume: 141
number: 12
pagerange: 3428-3442
event_location: England
issn: 1460-2156
citation:        Clayton, EL;    Milioto, C;    Muralidharan, B;    Norona, FE;    Edgar, JR;    Soriano, A;    Jafar-Nejad, P;             ... Isaacs, AM; + view all <#>        Clayton, EL;  Milioto, C;  Muralidharan, B;  Norona, FE;  Edgar, JR;  Soriano, A;  Jafar-Nejad, P;  Rigo, F;  Collinge, J;  Isaacs, AM;   - view fewer <#>    (2018)    Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown.                   Brain , 141  (12)   pp. 3428-3442.    10.1093/brain/awy284 <https://doi.org/10.1093/brain%2Fawy284>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10063313/1/awy284.pdf
document_url: https://discovery.ucl.ac.uk/id/eprint/10063313/6/awy284_suppl_data.pdf