Menozzi, E;
Schapira, AH;
(2020)
Enhancing the Activity of Glucocerebrosidase as a Treatment for Parkinson Disease.
CNS Drugs
, 34
(9)
pp. 915-923.
10.1007/s40263-020-00746-0.
Preview |
Text
Menozzi_Manuscript.R1_Clean.Copy.pdf - Accepted Version Download (583kB) | Preview |
Abstract
Mutations in the glucocerebrosidase (GBA1) gene are the most common genetic risk factor for Parkinson disease (PD). Homozygous or compound heterozygous GBA1 mutations cause the lysosomal storage disorder Gaucher disease (GD), characterized by deficient activity of the glucocerebrosidase enzyme (GCase). Both individuals with GD type I and heterozygous carriers of pathogenic variants of GBA1 have an increased risk of developing PD, by approximately ten- to 20-fold compared to non-carriers. GCase activity is also reduced in PD patients without GBA1 mutations, suggesting that the GCase lysosomal pathway might be involved in PD pathogenesis. Available evidence indicates that GCase can affect α-synuclein pathology in different ways. Misfolded GCase proteins are retained in the endoplasmic reticulum, altering the lysosomal trafficking of the enzyme and disrupting protein trafficking. Also, deficient GCase leads to accumulation of substrates that in turn may bind α-synuclein and promote pathological formation of aggregates. Furthermore, α-synuclein itself can lower the enzymatic activity of GCase, indicating that a bidirectional interaction exists between GCase and α-synuclein. Targeted therapies aimed at enhancing GCase activity, augmenting the trafficking of misfolded GCase proteins by small molecule chaperones, or reducing substrate accumulation, have been tested in preclinical and clinical trials. This article reviews the molecular mechanisms linking GCase to α-synuclein and discusses the therapeutic drugs that by targeting the GCase pathway can influence PD progression.
| Type: | Article |
|---|---|
| Title: | Enhancing the Activity of Glucocerebrosidase as a Treatment for Parkinson Disease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1007/s40263-020-00746-0 |
| Publisher version: | http://dx.doi.org/10.1007/s40263-020-00746-0 |
| 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: | ALPHA-SYNUCLEIN PATHOLOGY, GAUCHER-DISEASE, PHARMACOLOGICAL CHAPERONE, DOPAMINERGIC-NEURONS, GENE-THERAPY, MOUSE MODEL, GBA, MUTATION, EXPRESSION, 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/10112213 |
Archive Staff Only
 |
View Item |
