Gegg, ME;
Verona, G;
Schapira, AHV;
(2020)
Glucocerebrosidase deficiency promotes release of α-synuclein fibrils from cultured neurons.
Human Molecular Genetics
, Article ddaa085. 10.1093/hmg/ddaa085.
(In press).
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Abstract
Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the most important genetic risk factor for Parkinson disease (PD). GCase activity is also decreased in sporadic PD brains and with normal aging. Loss of GCase activity impairs the autophagy lysosomal pathway resulting in increased α-synuclein (α-syn) levels. Furthermore, elevated α-syn results in decreased GCase activity. While the role of α-syn in PD remains unclear, evidence indicates that aggregated α-syn fibrils are a pathogenic species in PD, passing between neurons and inducing endogenous native α-syn to aggregate; spreading pathology through the brain. We have investigated if preformed α-syn fibrils (PFFs) impair GCase activity in mouse cortical neurons and differentiated dopaminergic cells, and whether GCase deficiency in these models increased the transfer of α-syn pathology to naïve cells. Neurons treated with PFFs induced endogenous α-syn to become insoluble and phosphorylated at Ser129 to a greater extent than monomeric α-syn-treatment. PFFs, but not monomeric α-syn, inhibited lysosomal GCase activity in these cells and induced the unfolded protein response. Neurons in which GCase was inhibited by conduritol β-epoxide did not increase the amount of insoluble monomeric α-syn or its phosphorylation status. Instead the release of α-syn fibrils from GCase deficient cells was significantly increased. Co-culture studies showed that the transfer of α-syn pathology to naïve cells was greater from GCase deficient cells. This study suggests that GCase deficiency increases the spread of α-syn pathology and likely contributes to the earlier age of onset and increased cognitive decline associated with GBA-PD.
| Type: | Article |
|---|---|
| Title: | Glucocerebrosidase deficiency promotes release of α-synuclein fibrils from cultured neurons |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/hmg/ddaa085 |
| Publisher version: | https://doi.org/10.1093/hmg/ddaa085 |
| Language: | English |
| Additional information: | 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. |
| Keywords: | aging, dopamine, gaucher disease, parkinson disease, mutation, age of onset, autophagy, coculture techniques, epoxy compounds, genes, glucosylceramidase, neurons, phosphorylation ,brain, enzymes, mice, pathology, cognitive impairment, genetic risk, unfolded protein response, transfer technique, fibril |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences 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 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 > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10097778 |
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