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Ambroxol reverses tau and α-synuclein accumulation in a cholinergic N370S GBA1 mutation model

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. (In press). Green open access

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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.

Type: Article
Title: Ambroxol reverses tau and α-synuclein accumulation in a cholinergic N370S GBA1 mutation model
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddac038
Publisher version: https://doi.org/10.1093/hmg/ddac038
Language: English
Additional information: © 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/).
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10144197
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