eprintid: 10144197
rev_number: 14
eprint_status: archive
userid: 699
dir: disk0/10/14/41/97
datestamp: 2022-02-24 11:14:19
lastmod: 2022-04-20 17:02:36
status_changed: 2022-02-24 11:14:19
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Yang, Shi Yu
creators_name: Taanman, Jan-Willem
creators_name: Gegg, Matthew
creators_name: Schapira, Anthony HV
title: Ambroxol reverses tau and α-synuclein accumulation in a cholinergic N370S GBA1 mutation model
ispublished: inpress
divisions: C07
divisions: F84
divisions: B02
divisions: UCL
divisions: D07
note: © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).
abstract: Cognitive impairment is a common non-motor complication of Parkinson disease (PD). Glucocerebrosidase gene (GBA1) variants are found in 10–15% of PD cases and are numerically the most important risk factor for PD and dementia with Lewy bodies. Accumulation of α-synuclein and tau pathology is thought to underlie cognitive impairment in PD, and likely involves cholinergic as well as dopaminergic neurons. Neural crest stem cells were isolated from both PD patients with the common heterozygous N370S GBA1 mutation and normal subjects without GBA1 mutations. The stem cells were used to generate a cholinergic neuronal cell model. The effects of the GBA1 variant on glucocerebrosidase (GCase) protein and activity, and cathepsin D, tau and α-synuclein protein levels in cholinergic neurons were examined. Ambroxol, a GCase chaperone, was used to investigate whether GCase enhancement was able to reverse the effects of the GBA1 variant on cholinergic neurons. Significant reductions in GCase protein and activity, as well as in Cathepsin D levels were found in GBA1 mutant (N370S/WT) cholinergic neurons. Both tau and α-synuclein levels were significantly increased in GBA1 mutant (N370S/WT) cholinergic neurons. Ambroxol significantly enhanced GCase activity and decreased both tau and α-synuclein levels in cholinergic neurons. GBA1 mutations interfere with the metabolism of α-synuclein and tau proteins and induce higher levels of α-synuclein and tau proteins in cholinergic neurons. The GCase pathway provides a potential therapeutic target for neurodegenerative disorders related to pathological α-synuclein or tau accumulation.
date: 2022-02-18
date_type: published
publisher: Oxford University Press (OUP)
official_url: https://doi.org/10.1093/hmg/ddac038
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1940443
doi: 10.1093/hmg/ddac038
medium: Print-Electronic
pii: 6530531
lyricists_name: Gegg, Matthew
lyricists_id: MEGEG36
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Human Molecular Genetics
event_location: England
citation:        Yang, Shi Yu;    Taanman, Jan-Willem;    Gegg, Matthew;    Schapira, Anthony HV;      (2022)    Ambroxol reverses tau and α-synuclein accumulation in a cholinergic N370S GBA1 mutation model.                   Human Molecular Genetics        10.1093/hmg/ddac038 <https://doi.org/10.1093/hmg%2Fddac038>.    (In press).    Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10144197/1/ddac038%20VoR.pdf