eprintid: 10144622 rev_number: 7 eprint_status: archive userid: 699 dir: disk0/10/14/46/22 datestamp: 2022-03-04 13:34:07 lastmod: 2022-03-04 13:34:07 status_changed: 2022-03-04 13:34:07 type: article metadata_visibility: show sword_depositor: 699 creators_name: Gegg, ME creators_name: Menozzi, E creators_name: Schapira, AHV title: Glucocerebrosidase-associated Parkinson disease: Pathogenic mechanisms and potential drug treatments ispublished: pub divisions: C07 divisions: F84 divisions: B02 divisions: UCL divisions: D07 keywords: Parkinson disease, α-synuclein, Lysosome, Autophagy, Lipid, Neuroinflammation, Glucocerebrosidase note: © 2022 The Authors. Published by Elsevier Inc. under a Creative Commons license (https://creativecommons.org/licenses/by-nc-nd/4.0/). abstract: Dysfunction of the endolysosomal system is implicated in the pathogenesis of both sporadic and familial Parkinson disease (PD). Variants in genes encoding lysosomal proteins have been estimated to be associated with more than half of PD cases. The most common genetic risk factor for PD are variants in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. In this review we will describe the clinical symptoms and pathology of GBA-PD, and how this might be affected by the type of GBA variant. The putative mechanisms by which GCase deficiency in neurons and glia might contribute to PD pathogenesis will then be discussed, with particular emphasis on the accumulation of α-synuclein aggregates and the spread of pathogenic α-synuclein species between the cell types. The dysregulation of not only sphingolipids, but also phospholipids and cholesterol in the misfolding of α-synuclein is reviewed, as are neuroinflammation and the interaction of GCase with LRRK2 protein, another important contributor to PD pathogenesis. Study of both non-manifesting GBA carriers and GBA-PD cohorts provides an opportunity to identify robust biomarkers for PD progression as well as clinical trials for potential treatments. The final part of this review will describe preclinical studies and clinical trials for increasing GCase activity or reducing toxic substrate accumulation. date: 2022-05 date_type: published publisher: Elsevier BV official_url: https://doi.org/10.1016/j.nbd.2022.105663 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1942412 doi: 10.1016/j.nbd.2022.105663 lyricists_name: Gegg, Matthew lyricists_name: Menozzi, Elisa lyricists_id: MEGEG36 lyricists_id: EMENO65 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Neurobiology of Disease volume: 166 article_number: 105663 citation: Gegg, ME; Menozzi, E; Schapira, AHV; (2022) Glucocerebrosidase-associated Parkinson disease: Pathogenic mechanisms and potential drug treatments. Neurobiology of Disease , 166 , Article 105663. 10.1016/j.nbd.2022.105663 <https://doi.org/10.1016/j.nbd.2022.105663>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10144622/1/1-s2.0-S0969996122000547-main.pdf