The Double Toxic MPTP+CBE Presymptomatic Parkinson-Like Phenotype in Mice

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Sofya N. Pchelina^1,2,a*, Anastasia I. Bezrukova^1,2, Margarita M. Rudenok³, Alexander S. Zhuravlev^1,2, Ivan N. Rybolovlev³, Anna O. Lavrinova^1,2, Galina V. Baydakova⁴, Mikhail A. Nikolaev^1,2, Maxim S. Nesterov⁵, Denis A. Abaimov⁶, Victoria N. Pidurchina¹, Suzanna A. Partevyan³, Ekaterina I. Semenova³, Tatiana S. Usenko^1,2, Ekaterina Y. Zakharova³, Anton K. Emelyanov^1,2, Maria I. Shadrina³, and Petr A. Slominsky³

¹Petersburg Nuclear Physics Institute, Kurchatov Institute National Research Center, 188300 Gatchina, Russia

²Pavlov First Saint Petersburg State Medical University, 197022 Saint Petersburg, Russia

³Institute of Molecular Genetics, Kurchatov Institute National Research Centre, 123182 Moscow, Russia

⁴Research Center of Medical Genetics, 115522 Moscow, Russia

⁵Scientific Center of Biomedical Technologies, Federal Medical and Biological Agency of Russia, 143442 Moscow, Russia

⁶Research Centre of Neurology, 125367 Moscow, Russia

^* To whom correspondence should be addressed.

Received: March 26, 2025; Revised: July 10, 2025; Accepted: July 15, 2025

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The deficiency of glucocerebrosidase (GCase) encoded by the GBA1 gene, leads to the autosomal recessive Gaucher disease and highly increased risk of developing Parkinson’s disease (PD). In order to study the effect of GCase dysfunction on neurodegeneration, we evaluated the GCase activity, lysosphingolipid content, extent of dopaminergic neuron degeneration in the substantia nigra (SN), and levels of dopamine (DA) and total and oligomeric α-synuclein (α-Syn) in the brain of mice with the presymptomatic stage of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in combination with a single injection of the GCase selective inhibitor conduritol-β-epoxide (CBE) (100 mg/kg body weight). A single injection of CBE led to a ~50% decrease in the GCase activity, significant increase in the lysosphingolipid content, and striatal accumulation of oligomeric α-Syn in the mouse brain. Assessment of the DA neuron degeneration in the SN 14 days after injection by immunohistochemical staining for tyrosine hydroxylase (TH) demonstrated a twice more pronounced reduction in the number of TH+ neurons in MPTP+CBE mice compared to MPTP only-treated animals (14% vs. 29%, respectively; p < 0.0001). The double neurotoxic (MPTP+CBE) model was also characterized by a decrease in the DA content and more pronounced accumulation of total α-Syn in the striatum. Overall, we demonstrated that inhibition of the GCase activity leads to the α-Syn accumulation and further exacerbation of the MPTP-induced pathology. The described double toxic MPTP+CBE mouse model can be used for the screening of neuroprotective drugs in approaches aimed at increasing the GCase activity.

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KEY WORDS: Parkinson’s disease, glucocerebrosidase, CBE, MPTP, mouse model

DOI: 10.1134/S000629792560070X

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