Objective: Reduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson's disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson's Progression Markers Initiative (PPMI) cohort.
Methods: We measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, n = 392; controls, n = 175) were fully sequenced for GBA variants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing.
Results: Fifty-two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n = 20; controls, n = 5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/L/h vs. 11.68 µmol/L/h, P = 0.035). Glucocerebrosidase activity was moderately (r = 0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson's Disease Rating Scale motor score in the "off" medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time.
Interpretation: GCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545591 | PMC |
| http://dx.doi.org/10.1002/acn3.51164 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Developing Allosteric Chaperones for -Associated Disorders-An Integrated Computational and Experimental Approach.
Int J Mol Sci
December 2024
Gain Therapeutics Sucursal en España, Parc Científic de Barcelona, 08028 Barcelona, Spain.
Mutations in the gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are associated with Gaucher disease and increased risk of Parkinson's disease. This study describes the discovery and characterization of novel allosteric pharmacological chaperones for GCase through an innovative computational approach combined with experimental validation. Utilizing virtual screening and structure-activity relationship optimization, researchers identified several compounds that significantly enhance GCase activity and stability across various cellular models, including patient-derived fibroblasts and neuronal cells harboring mutations.
View Article and Find Full Text PDFIncreased α-synuclein phosphorylation and oligomerization and altered enzymes in plasma of patients with Parkinson's disease.
Neuroscience
December 2024
Department of Neurobiology and National Clinical Research Center for Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China; Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China; Beijing Key Laboratory for Parkinson's Disease, Beijing, China. Electronic address:
The brain of patients with Parkinson's disease (PD) was characterized by increased phosphorylation and oligomerization of α-synuclein (α-syn) and altered activity of enzymes regulating α-syn phosphorylation and oligomerization. Whether increased α-syn phosphorylation and oligomerization as well as related enzyme changes can be detected in the plasma of PD patients remains unclear. Here, we showed that human α-syn proteins incubated in PD plasma formed more oligomerized α-syn (O-α-syn) and phosphorylated α-syn (pS-α-syn) than those in healthy control (HC) plasma.
View Article and Find Full Text PDFDeciphering metabolic shifts in Gaucher disease type 1: a multi-omics study.
J Mol Med (Berl)
December 2024
Department of Metabolic Biochemistry, Referral Center for Lysosomal Diseases, Normandie Univ, UNIROUEN, CHU Rouen, INSERM U1245, Filière G2M, 76000, Rouen, France.
Gaucher disease (GD), an autosomal recessive lysosomal disorder, primarily affects the lysosomal enzyme β-glucocerebrosidase (GCase), leading to glucosylceramide accumulation in lysosomes. GD presents a wide spectrum of clinical manifestations. This study deploys immune-based proteomics and mass spectrometry-based metabolomics technologies to comprehensively investigate the biochemical landscape in 43 deeply phenotyped type 1 GD patients compared to 59 controls.
View Article and Find Full Text PDFMultivalent GCase Enhancers: Synthesis and Evaluation of Glyco-Gold Nanoparticles Decorated with Trihydroxypiperidine Iminosugars.
Bioconjug Chem
January 2025
Department of Chemistry "Ugo Schiff" (DICUS), University of Florence, Via della Lastruccia 3-13, Sesto Fiorentino, FI 50019, Italy.
The present study reports the preparation of the first multivalent iminosugars built onto a glyco-gold nanoparticle core (glyco-AuNPs) capable of stabilizing or enhancing the activity of the lysosomal enzyme GCase, which is defective in Gaucher disease. An -nonyltrihydroxypiperidine was selected as the bioactive iminosugar unit and further functionalized, via copper-catalyzed alkyne-azide cycloaddition, with a thiol-ending linker that allowed the conjugation to the gold core. These bioactive ligands were obtained with either a linear monomeric or dendritic trimeric arrangement of the iminosugar.
View Article and Find Full Text PDFProtective Effects of Ambroxol on Aβ and α-Synuclein-Induced Neurotoxicity Through Glucocerebrosidase Activation in HT-22 Hippocampal Neuronal Cells.
Int J Mol Sci
November 2024
Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan.
Article Synopsis
- Dementia with Lewy bodies (DLB) is a serious brain disorder characterized by the build-up of harmful proteins, including α-synuclein and amyloid β, leading to neuron death and a strong need for better treatments.
- The drug Ambroxol (AMBX) has shown promise in activating an enzyme called glucocerebrosidase, which helps clear toxic protein aggregates and improve cell health.
- In tests with brain cells exposed to these harmful proteins, AMBX was found to increase cell viability, restore enzyme activity, promote waste clearance, and reduce damage, indicating its potential as a treatment for DLB that needs further exploration in animal studies and clinical trials.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!