eprintid: 10025253 rev_number: 33 eprint_status: archive userid: 608 dir: disk0/10/02/52/53 datestamp: 2017-10-23 14:18:09 lastmod: 2021-09-19 22:15:04 status_changed: 2017-10-23 14:18:09 type: article metadata_visibility: show creators_name: Migdalska-Richards, A creators_name: Wegrzynowicz, M creators_name: Rusconi, R creators_name: Deangeli, G creators_name: Di Monte, DA creators_name: Spillantini, MG creators_name: Schapira, AHV title: The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F84 keywords: glucocerebrosidase, GBA1, alpha-synuclein, Parkinson’s disease, neurodegeneration note: Copyright © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. 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 glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson's disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson's disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels. We then investigated the effect of overexpression of human alpha-synuclein in the substantia nigra of aged (18 to 21-month-old) L444P Gba1 mice. Following intraparenchymal injections of human alpha-synuclein carrying viral vectors, pathological accumulation of phosphorylated alpha-synuclein occurred within the transduced neurons. Stereological counts of nigral dopaminergic neurons revealed a significantly greater cell loss in Gba1-mutant than wild-type mice. These results indicate that Gba1 deficiency enhances neuronal vulnerability to neurodegenerative processes triggered by increased alpha-synuclein expression. date: 2017-10 date_type: published official_url: https://doi.org/10.1093/brain/awx221 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: 1426360 doi: 10.1093/brain/awx221 pii: 4106291 lyricists_name: Migdalska Richards, Anna lyricists_name: Schapira, Anthony lyricists_id: AMIGD16 lyricists_id: AHVSC78 actors_name: Bracey, Alan actors_id: ABBRA90 actors_role: owner full_text_status: public publication: Brain volume: 140 number: 10 pagerange: 2706-2721 event_location: England issn: 1460-2156 citation: Migdalska-Richards, A; Wegrzynowicz, M; Rusconi, R; Deangeli, G; Di Monte, DA; Spillantini, MG; Schapira, AHV; (2017) The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice. Brain , 140 (10) pp. 2706-2721. 10.1093/brain/awx221 <https://doi.org/10.1093/brain%2Fawx221>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10025253/1/awx221.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/10025253/7/Migdalska-Richards_L444P_Gba1_mutation_Suppl.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/10025253/8/Migdalska-Richards_L444P_Gba1_mutation_S1.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/10025253/9/Migdalska-Richards_L444P_Gba1_mutation_S2.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/10025253/10/Migdalska-Richards_L444P_Gba1_mutation_S3.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/10025253/11/Migdalska-Richards_L444P_Gba1_mutation_S4.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/10025253/12/Migdalska-Richards_L444P_Gba1_mutation_Tables.pdf