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Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

Abstract (Expand)

Abstract Rare variants in the beta-glucocerebrosidase gene ( GBA1 ) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease …hich often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

Authors: Muhammad Aslam, Nirosiya Kandasamy, Anwar Ullah, Nagarajan Paramasivam, Mehmet Ali Öztürk, Saima Naureen, Abida Arshad, Mazhar Badshah, Kafaitullah Khan, Muhammad Wajid, Rashda Abbasi, Muhammad Ilyas, Roland Eils, Matthias Schlesner, Rebecca C. Wade, Nafees Ahmad, Jakob von Engelhardt

Date Published: 1st Dec 2021

Publication Type: Journal

Contact Map Fingerprints of Protein–Ligand Unbinding Trajectories Reveal Mechanisms Determining Residence Times Computed from Scaled Molecular Dynamics

Abstract

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Authors: Marc Bianciotto, Paraskevi Gkeka, Daria B. Kokh, Rebecca C. Wade, Hervé Minoux

Date Published: 12th Oct 2021

Publication Type: Journal

G Protein-Coupled Receptor–Ligand Dissociation Rates and Mechanisms from τRAMD Simulations

Abstract

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Authors: Daria B. Kokh, Rebecca C. Wade

Date Published: 12th Oct 2021

Publication Type: Journal

DNA sequence-dependent positioning of the linker histone in a nucleosome: A single-pair FRET study

Abstract

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Authors: Madhura De, Mehmet Ali Öztürk, Sebastian Isbaner, Katalin Tóth, Rebecca C. Wade

Date Published: 1st Sep 2021

Publication Type: Journal

Prediction of the Drug–Target Binding Kinetics for Flexible Proteins by Comparative Binding Energy Analysis

Abstract

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Authors: Ariane Nunes-Alves, Fabian Ormersbach, Rebecca C. Wade

Date Published: 26th Jul 2021

Publication Type: Journal

A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics

Abstract

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Authors: Jonas Gossen, Simone Albani, Anton Hanke, Benjamin P. Joseph, Cathrine Bergh, Maria Kuzikov, Elisa Costanzi, Candida Manelfi, Paola Storici, Philip Gribbon, Andrea R. Beccari, Carmine Talarico, Francesca Spyrakis, Erik Lindahl, Andrea Zaliani, Paolo Carloni, Rebecca C. Wade, Francesco Musiani, Daria B. Kokh, Giulia Rossetti

Date Published: 11th Jun 2021

Publication Type: Journal

Brownian Dynamics Simulations of Proteins in the Presence of Surfaces: Long-Range Electrostatics and Mean-Field Hydrodynamics

Abstract

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Authors: Martin Reinhardt, Neil J. Bruce, Daria B. Kokh, Rebecca C. Wade

Date Published: 8th Jun 2021

Publication Type: Journal

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