{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», 188300 Gatchina, Russia",
    "Department of Molecular Genetic and Nanobiological Technologies, Scientific Research Center, Pavlov First Saint-Petersburg State Medical University, 197022 Saint-Petersburg, Russia",
    "Higher School of Biomedical Systems and Technologies, Institute of Biomedical Systems and Biotechnology, Peter the Great Saint-Petersburg Polytechnic University, 195251 Saint-Petersburg, Russia",
    "National Research Center «Kurchatov Institute», 123182 Moscow, Russia",
    "Department of Organic Chemistry, Saint Petersburg State Institute of Technology (Technical University), 190013 Saint-Petersburg, Russia",
    "Laboratory of Nanobiotechnologies, Alferov University, 194021 Saint-Petersburg, Russia",
    "Research Centre for Medical Genetics, 115522 Moscow, Russia",
    "Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia",
    "N.P. Bechtereva Institute of the Human Brain of Russian Academy of Sciences, 197376 Saint-Petersburg, Russia",
    "Scientific Center of Biomedical Technologies, Federal Medical and Biological Agency of Russia, 143442 Moscow, Russia",
    "Research Centre of Neurology, 125367 Moscow, Russia",
    "Almazov National Medical Research Centre, 197341 Saint-Petersburg, Russia",
    "Department of Neurology, Pavlov First Saint-Petersburg State Medical University, 197022 Saint-Petersburg, Russia"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 30,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Anton Emelyanov"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Alena Kopytova",
      "orcid": "0000-0002-6557-0253"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Anna Lavrinova",
      "orcid": "0009-0007-2824-5762"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Georgy Rychkov",
      "orcid": "0000-0003-2767-9175"
    },
    {
      "affs": [
        3
      ],
      "name": "Margarita Rudenok"
    },
    {
      "affs": [
        3
      ],
      "name": "Ivan Rybolovlev"
    },
    {
      "affs": [
        0
      ],
      "name": "Farid Ibatullin"
    },
    {
      "affs": [
        0
      ],
      "name": "Victoria Pidyurchina",
      "orcid": "0009-0001-6917-3693"
    },
    {
      "affs": [
        0
      ],
      "name": "Alexandra Artynyuk"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Mikhail Nikolaev",
      "orcid": "0000-0002-1952-4678"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Anastasia Bezrukova"
    },
    {
      "affs": [
        4
      ],
      "name": "Alexander Stepakov"
    },
    {
      "affs": [
        5
      ],
      "name": "Vitali Boitsov",
      "orcid": "0000-0002-4857-2046"
    },
    {
      "affs": [
        6
      ],
      "name": "Galina Baydakova"
    },
    {
      "affs": [
        7
      ],
      "name": "Elena Grigor’eva",
      "orcid": "0000-0002-9162-9108"
    },
    {
      "affs": [
        7
      ],
      "name": "Sophia Pavlova",
      "orcid": "0000-0003-1095-3692"
    },
    {
      "affs": [
        3
      ],
      "name": "Suzanna Partevian",
      "orcid": "0000-0001-7691-7796"
    },
    {
      "affs": [
        3
      ],
      "name": "Ekaterina Semenova",
      "orcid": "0000-0001-6145-0476"
    },
    {
      "affs": [
        8
      ],
      "name": "Irina Miliukhina"
    },
    {
      "affs": [
        9
      ],
      "name": "Maxim Nesterov"
    },
    {
      "affs": [
        10
      ],
      "name": "Denis Abaimov",
      "orcid": "0000-0001-6888-3223"
    },
    {
      "affs": [
        11
      ],
      "name": "Vadim Bezrukikh"
    },
    {
      "affs": [
        12
      ],
      "name": "Alla Timofeeva"
    },
    {
      "affs": [
        0
      ],
      "name": "Varvara Kvanchiani"
    },
    {
      "affs": [
        0
      ],
      "name": "Ekaterina Sergeeva"
    },
    {
      "affs": [
        3
      ],
      "name": "Maria Shadrina"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Tatiana Usenko",
      "orcid": "0000-0002-5132-2283"
    },
    {
      "affs": [
        6
      ],
      "name": "Ekaterina Zakharova"
    },
    {
      "affs": [
        3
      ],
      "name": "Petr Slominsky",
      "orcid": "0000-0003-3530-0655"
    },
    {
      "affs": [
        0,
        1,
        6
      ],
      "name": "Sofya Pchelina",
      "orcid": "0000-0001-7431-6014"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8zwm9y7byc4b9.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27219602",
  "fulltext_url": null,
  "id": "8zwm9y7byc4b9",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/21/9602",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Lysosomal Storage Disorders Research"
    ]
  ],
  "openalex": "W7224014623",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-27",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/8zwm9y7byc4b9.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:57Z",
      "native_id": "10.3390/ijms27219602",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/21/9602"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Lysosomal Storage Disorders Research",
      "subfield": "physiology"
    }
  ],
  "title": "A Novel Glucocerebrosidase Allosteric Activator Prevents MPTP-Induced Neurodegeneration in Mice",
  "title_text": "A Novel Glucocerebrosidase Allosteric Activator Prevents MPTP-Induced Neurodegeneration in Mice",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:57Z",
  "url": "https://research.draconitic.com/paper/8zwm9y7byc4b9",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}