Exploring the relationship betweenGBA1host genotype and gut microbiome in theGBA1L444P/WTmouse model: Implications for Parkinson disease pathogenesis DOI Creative Commons
Elisa Menozzi,

Mallia Geiger,

Victoria Meslier

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 15, 2024

Abstract Background Heterozygous variants in GBA1 are the commonest genetic risk factor for Parkinson disease (PD) but penetrance is incomplete. dysfunction can cause gastrointestinal disturbances and microbiome changes preclinical models. Mounting evidence suggests that microbiota-gut-brain axis potentially implicated PD pathogenesis. Whether gut composition influenced by host genetics heterozygosis has never been explored. Objectives To evaluate whether heterozygosity pathogenic L444P variant perturbations composition. Methods Faecal samples collected from L444P/WT WT/WT mice at 3 6 months of age were analysed through shotgun metagenomic sequencing. Results No differences α- β-diversity detected between genotyped groups, either time points. Overall, we found a little variation functional potential over time. Conclusion Host genotype does not impact structure presented mouse model. Studies investigating effect second hit on physiology could explain partial PD.

Язык: Английский

Parkinson’s disease and metabolic disorders, understanding their shared co-morbidity through the autonomic nervous system DOI

Thanh Pham,

Rebecca E. Schelling,

Ken H. Loh

и другие.

Advances in genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Evidence of α-Synuclein/Glucocerebrosidase Dual Targeting by Iminosugar Derivatives DOI Creative Commons

Giuseppe Tagliaferro,

Maria Giulia Davighi, Francesca Clemente

и другие.

ACS Chemical Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Intrinsically disordered proteins (IDPs) are highly flexible molecules often linked to the onset of incurable diseases. Despite their great therapeutic potential, IDPs considered as undruggable because they lack defined binding pockets, which constitute basis drug discovery approaches. However, small that interact with intrinsically state α-synuclein, protein Parkinson's disease (PD), were recently identified and shown act chemical chaperones. Glucocerebrosidase (GCase) is an enzyme crucially involved in PD, since mutations code for GCase among most frequent genetic risk factors PD. Following "dual-target" approach, stating one carefully designed molecule can, principle, interfere more than target, we a pharmacological chaperone interacts monomeric form α-synuclein. This result opens novel avenues be explored search on dual targets, particular, challenging targets such IDPs.

Язык: Английский

Процитировано

0
A PheWAS approach to identify associations of GBA1 variants with comprehensive phenotypes beyond neurological diseases DOI Creative Commons
Jia-Qi Yang,

Yuanfeng Huang,

Zheng Wang

и другие.

npj Parkinson s Disease, Год журнала: 2025, Номер 11(1)

Опубликована: Март 17, 2025

Given the established association between numerous GBA1 variants and specific neurological diseases, we extended exploration by a phenome-wide study to assess impact of on wider spectrum health-related traits. We identified 41 phenotypes associated with variants, 39 which were unreported, including 21 non-neurological 20 phenotypes. Based variant-level tests, found beyond particularly decreased gray-white matter contrast measures across 13 distinct brain regions, non-coding variant rs9628662 was six traits such as hypermetropia. Another rs3115534 showed associations eight biomarkers multiple categories, an increased risk benign digestive neoplasms. Notably, compared protein-coding p.T408M, had opposing effects three hematological biomarkers. Additionally, gene-level analyses revealed significant diseases Parkinson's disease. The findings demonstrated that significantly various

Язык: Английский

Процитировано

0
Acetal functionalized iminosugars for targeting β-glucocerebrosidase modulation DOI Creative Commons
Maria Giulia Davighi, Francesca Clemente, Camilla Matassini

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 117529 - 117529

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
Genetics of movement disorders - outline of current options and upcoming diagnostic trends for clinical neurologists DOI
Miriam Ostrožovičová, Matěj Škorvánek

Neurologie pro praxi, Год журнала: 2025, Номер 26(1), С. 37 - 42

Опубликована: Март 19, 2025

Язык: Английский

Процитировано

0
A Multi-Omics-Empowered Framework for Precision Diagnosis and Treatment of Lysosomal Diseases DOI Creative Commons
Nguyen Thi Hai Yen,

Nguyen Tran Nam Tien,

Nguyen Quang Thu

и другие.

Journal of Pharmaceutical Analysis, Год журнала: 2025, Номер unknown, С. 101274 - 101274

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2 DOI Creative Commons

Jan Philipp Dobert,

Jan-Hannes Schäfer, Thomas Dal Maso

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 30, 2025

Abstract Targeting proteins to their final cellular destination requires transport mechanisms and nearly all lysosomal enzymes reach the lysosome via mannose-6-phosphate receptor pathway. One of few known exceptions is enzyme β-glucocerebrosidase (GCase) that integral membrane protein type-2 (LIMP-2) as a proprietary transporter. Genetic variations in GCase encoding gene GBA1 cause Gaucher’s disease (GD) present highest genetic risk factor develop Parkinson’s (PD). Activators targeting emerge promising therapeutic approach treat GD PD, with pre-clinical clinical trials ongoing. In this study, we resolve complex LIMP-2 using cryo-electron microscopy aid an engineered shuttle two GCase-targeted pro-macrobodies. We identify helix 5 7 interact binding pocket GCase, forming mostly hydrophobic interaction interface supported by one essential salt bridge. Understanding interplay on structural level crucial potential activation sites conceptualizing novel approaches GCase. Here, unveil structure mannose-6-phosphate-independent provide fundamental knowledge for translational research overcome PD.

Язык: Английский

Процитировано

0
Diet, β-glucocerebrosidase deficiency, and Parkinson’s disease DOI Creative Commons
James A. Shayman

Journal of Lipid Research, Год журнала: 2024, Номер unknown, С. 100689 - 100689

Опубликована: Окт. 1, 2024

Язык: Английский

Процитировано

0
Monogenic Parkinson's Disease and the Impact of APOE E4: A Case-Control Study DOI Creative Commons
Matthew J. Kmiecik, Michael V. Holmes, Pierre Fontanillas

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 16, 2024

Abstract Importance The lack of information on progression, phenoconversion, and risk dementia in a large genotyped sample impedes reliable enrichment for early interventional trials Parkinson’s disease (PD). Objective To investigate PD penetrance, risk, motor/non-motor phenotypes, APOE allele effects LRRK2 G2019S GBA N370S carriers. Design Observational longitudinal case-control self-report survey study. Setting A US population-based study cohort enrolled the 23andMe, Inc. Fox Insight Genetic Substudy (FIGS) databases. Participants total included 7,586,842 participants ( n =35,163 PD; 27% cases from FIGS); 8,791 carriers (565 with PD), 37,427 (524 244 dual (37 7.5 million non-carriers (34,037 PD). Exposure(s) G2019S, N370S, E2/E3/E4 alleles polygenic scores (PRS). Main Outcome(s) Measure(s) Cumulative incidence was estimated using Kaplan-Meier accelerated failure time models. Relative odds developing motor non-motor symptoms were calculated logistic regression models according to genetic exposure. Impact dose-dependent analysis. Results By age 80 years, cumulative 43% carriers, 32% 6% 3% non-carriers. Higher PRS associated increased penetrance variants earlier diagnosis. Motor similar PD. highest burden symptoms, including REM sleep behavior disorder cognitive/memory deficits, lowest. E4 dosage greater hallucinations cognitive decline addition carrier status. Conclusions Relevance Our findings support use screening—including E4, PRS—to enrich candidate selection neuroprotective better define outcome measures based factors.

Язык: Английский

Процитировано

0
Multivalent GCase Enhancers: Synthesis and Evaluation of Glyco-Gold Nanoparticles Decorated with Trihydroxypiperidine Iminosugars DOI
Francesca Buco, Francesca Clemente, Amelia Morrone

и другие.

Bioconjugate Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 19, 2024

The present study reports the preparation of first multivalent iminosugars built onto a glyco-gold nanoparticle core (glyco-AuNPs) capable stabilizing or enhancing activity lysosomal enzyme GCase, which is defective in Gaucher disease. An N-nonyltrihydroxypiperidine was selected as bioactive iminosugar unit and further functionalized, via copper-catalyzed alkyne–azide cycloaddition, with thiol-ending linker that allowed conjugation to gold core. These ligands were obtained either linear monomeric dendritic trimeric arrangement iminosugar. concentration on surface modulated different amounts glucoside bearing short spacer inner ligand. new mixed-ligand coated glyco-AuNPs fully characterized, those highest colloidal stability aqueous medium subjected biological evaluation. Glyco-AuNPs units showed ability stabilize recombinant GCase thermal denaturation assay, while able enhance mutant patient's fibroblasts by 1.9-fold at 2.2 μM.

Язык: Английский

Процитировано

0