A Novel Glucocerebrosidase Allosteric Activator Prevents MPTP-Induced Neurodegeneration in Mice
13 affiliations
- 1Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», 188300 Gatchina, Russia
- 2Department of Molecular Genetic and Nanobiological Technologies, Scientific Research Center, Pavlov First Saint-Petersburg State Medical University, 197022 Saint-Petersburg, Russia
- 3Higher School of Biomedical Systems and Technologies, Institute of Biomedical Systems and Biotechnology, Peter the Great Saint-Petersburg Polytechnic University, 195251 Saint-Petersburg, Russia
- 4National Research Center «Kurchatov Institute», 123182 Moscow, Russia
- 5Department of Organic Chemistry, Saint Petersburg State Institute of Technology (Technical University), 190013 Saint-Petersburg, Russia
- 6Laboratory of Nanobiotechnologies, Alferov University, 194021 Saint-Petersburg, Russia
- 7Research Centre for Medical Genetics, 115522 Moscow, Russia
- 8Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
- 9N.P. Bechtereva Institute of the Human Brain of Russian Academy of Sciences, 197376 Saint-Petersburg, Russia
- 10Scientific Center of Biomedical Technologies, Federal Medical and Biological Agency of Russia, 143442 Moscow, Russia
- 11Research Centre of Neurology, 125367 Moscow, Russia
- 12Almazov National Medical Research Centre, 197341 Saint-Petersburg, Russia
- 13Department of Neurology, Pavlov First Saint-Petersburg State Medical University, 197022 Saint-Petersburg, Russia
Abstract
Mutations in the GBA1 gene, encoding lysosomal β-glucocerebrosidase (GCase), cause Gaucher disease (GD) and represent the most common genetic risk factor for Parkinson’s disease (PD). To target this pathway, therapeutic approaches for both GD and PD are actively being developed, focusing on two main drug classes: pharmacological chaperones (e.g., ambroxol) and allosteric GCase activators. Here, we characterize a novel allosteric GCase activator, N2, a derivative of the non-inhibitory chaperone NCGC607, and evaluate its therapeutic potential using computational, in vitro, and in vivo approaches. Molecular docking and molecular dynamics simulations indicated that N2 binds within the allosteric site of the mutant p.N370S GCase structure. In patient-derived cells (peripheral blood mononuclear cell-derived macrophages and induced pluripotent stem cell-derived dopaminergic neurons from GD and GBA1-PD patients), N2 enhanced GCase lysosomal translocation, modulated its enzymatic activity and protein level, and reduced substrate accumulation. Furthermore, we demonstrate for the first time that N2 exerts robust neuroprotective effects in an in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Specifically, N2 treatment attenuated MPTP-induced hexosylsphingosine accumulation in the prefrontal cortex, and ameliorated both tyrosine hydroxylase-positive neuronal loss in the substantia nigra and dopamine depletion in the striatum. Our findings first demonstrated the neuroprotective properties of a GCase allosteric activator on an MPTP-induced mouse model of PD and supported the emerging perspectives of such compounds for the treatment of GCase-related disorders.
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BibTeX
@article{emelyanov2026novel,
title = {{A Novel Glucocerebrosidase Allosteric Activator Prevents MPTP-Induced Neurodegeneration in Mice}},
author = {Anton Emelyanov and Alena Kopytova and Anna Lavrinova and Georgy Rychkov and Margarita Rudenok and Ivan Rybolovlev and Farid Ibatullin and Victoria Pidyurchina and Alexandra Artynyuk and Mikhail Nikolaev and Anastasia Bezrukova and Alexander Stepakov and Vitali Boitsov and Galina Baydakova and Elena Grigor’eva and Sophia Pavlova and Suzanna Partevian and Ekaterina Semenova and Irina Miliukhina and Maxim Nesterov and Denis Abaimov and Vadim Bezrukikh and Alla Timofeeva and Varvara Kvanchiani and Ekaterina Sergeeva and Maria Shadrina and Tatiana Usenko and Ekaterina Zakharova and Petr Slominsky and Sofya Pchelina},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219602},
url = {https://www.mdpi.com/1422-0067/27/21/9602},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A Novel Glucocerebrosidase Allosteric Activator Prevents MPTP-Induced Neurodegeneration in Mice
AU - Anton Emelyanov
AU - Alena Kopytova
AU - Anna Lavrinova
AU - Georgy Rychkov
AU - Margarita Rudenok
AU - Ivan Rybolovlev
AU - Farid Ibatullin
AU - Victoria Pidyurchina
AU - Alexandra Artynyuk
AU - Mikhail Nikolaev
AU - Anastasia Bezrukova
AU - Alexander Stepakov
AU - Vitali Boitsov
AU - Galina Baydakova
AU - Elena Grigor’eva
AU - Sophia Pavlova
AU - Suzanna Partevian
AU - Ekaterina Semenova
AU - Irina Miliukhina
AU - Maxim Nesterov
AU - Denis Abaimov
AU - Vadim Bezrukikh
AU - Alla Timofeeva
AU - Varvara Kvanchiani
AU - Ekaterina Sergeeva
AU - Maria Shadrina
AU - Tatiana Usenko
AU - Ekaterina Zakharova
AU - Petr Slominsky
AU - Sofya Pchelina
PY - 2026
DA - 2026/10/27
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219602
UR - https://www.mdpi.com/1422-0067/27/21/9602
AB - Mutations in the GBA1 gene, encoding lysosomal β-glucocerebrosidase (GCase), cause Gaucher disease (GD) and represent the most common genetic risk factor for Parkinson’s disease (PD). To target this pathway, therapeutic approaches for both GD and PD are actively being developed, focusing on two main drug classes: pharmacological chaperones (e.g., ambroxol) and allosteric GCase activators. Here, we characterize a novel allosteric GCase activator, N2, a derivative of the non-inhibitory chaperone NCGC607, and evaluate its therapeutic potential using computational, in vitro, and in vivo approaches. Molecular docking and molecular dynamics simulations indicated that N2 binds within the allosteric site of the mutant p.N370S GCase structure. In patient-derived cells (peripheral blood mononuclear cell-derived macrophages and induced pluripotent stem cell-derived dopaminergic neurons from GD and GBA1-PD patients), N2 enhanced GCase lysosomal translocation, modulated its enzymatic activity and protein level, and reduced substrate accumulation. Furthermore, we demonstrate for the first time that N2 exerts robust neuroprotective effects in an in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Specifically, N2 treatment attenuated MPTP-induced hexosylsphingosine accumulation in the prefrontal cortex, and ameliorated both tyrosine hydroxylase-positive neuronal loss in the substantia nigra and dopamine depletion in the striatum. Our findings first demonstrated the neuroprotective properties of a GCase allosteric activator on an MPTP-induced mouse model of PD and supported the emerging perspectives of such compounds for the treatment of GCase-related disorders.
SN - 1422-0067
ER -