Vieira, SRL;
Schapira, AHV;
(2021)
Glucocerebrosidase mutations: A paradigm for neurodegeneration pathways.
Free Radical Biology and Medicine
, 175
pp. 42-55.
10.1016/j.freeradbiomed.2021.08.230.
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Abstract
Biallelic (homozygous or compound heterozygous) glucocerebrosidase gene (GBA) mutations cause Gaucher disease, whereas heterozygous mutations are numerically the most important genetic risk factor for Parkinson disease (PD) and are associated with the development of other synucleinopathies, notably Dementia with Lewy Bodies. This phenomenon is not limited to GBA, with converging evidence highlighting further examples of autosomal recessive disease genes increasing neurodegeneration risk in heterozygous mutation carriers. Nevertheless, despite extensive research, the cellular mechanisms by which mutations in GBA, encoding lysosomal enzyme β-glucocerebrosidase (GCase), predispose to neurodegeneration remain incompletely understood. Alpha-synuclein (A-SYN) accumulation, autophagic lysosomal dysfunction, mitochondrial abnormalities, ER stress and neuroinflammation have been proposed as candidate pathogenic pathways in GBA-linked PD. The observation of GCase and A-SYN interactions in PD initiated the development and evaluation of GCase-targeted therapeutics in PD clinical trials.
| Type: | Article |
|---|---|
| Title: | Glucocerebrosidase mutations: A paradigm for neurodegeneration pathways |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.freeradbiomed.2021.08.230 |
| Publisher version: | https://doi.org/10.1016/j.freeradbiomed.2021.08.23... |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Glucocerebrosidase, Alpha-synuclein, Parkinson Disease, Gaucher Disease, Synucleinopathies, Dementia with Lewy Bodies, Neurodegeneration, Autosomal recessive, Ambroxol |
| 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 |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10166278 |
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