The precise etiology of Parkinson’s disease (PD) is still poorly understood, but it is thought to arise due to an intricate relationship between genes and the environment. Our study takes a unique approach to understanding the effect of environmental factors on the onset and progression of α-synuclein (aSyn) pathology, a key feature of PD, from the olfactory bulb (OB) to other brain regions. In the present study, we evaluated the time-dependent progression of PD-like pathology by administering rotenone intranasally for 5.5 months in C57BL/6 male mice.
We performed olfactory and motor tests and examined aSyn accumulation, glial cell activation, and dopaminergic (DAergic) neurodegeneration after 3, 4, and 5.5 months of rotenone exposure by immunoblotting and immunofluorescence techniques. We observed a time-dependent progression of aSyn accumulation from the OB to other brain regions, including the mid-brain and cortex. Consistently, we observed a time-dependent behavioral impairment, OB atrophy, progression of aSyn pathology, neuroinflammation, and neurodegeneration.
Our findings also established a link between distinct astrocyte activation and DAergic activity. In conclusion, this chronic and progressive mouse model mimics the brain-first type of progression of PD-like pathology in some PD patients, opening the possibility for testing potential disease-modifying interventions. This supplement was supported by the National Institute of Pharmaceutical Education and Research (NIPER) seed fund, Ahmedabad, Department of Pharmaceutics, Ministry of Chemicals and Fertilizers, Government of India.
Amit Khairnar gratefully acknowledges the support of the Ramalingaswami Fellowship (No. BT/RLF/Re-entry/24/2017) from the Department of Biotechnology, India. Khairnar would like to acknowledge project no.
LX22NPO5107 (MEYS): Financed by the European Union-Next Generation EU for support. The authors acknowledge the National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad administration for providing the facility and support for conducting this study. The authors also acknowledge the ISI-MR within the Czech-BioImaging large RI project (LM2023050), funded by the Ministry of Education, Youth and Sports of the Czech Republic, for supporting this study.
Present address: Department of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Texas, 78712, Austin, USA These authors contributed equally: Jhanvi Soni, Manasi Uttarkar. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, India Monika Sharma, Nishant Sharma, Jhanvi Soni, Manasi Uttarkar & Amit Khairnar Department of Pharmacology, Parul Institute of Pharmacy, Parul University, Vadodara, India Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czechia Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK Faculdade de Medicina e Ciências Biomédicas, Algarve Biomedical Center Research Institute, Universidade do Algarve, Faro, Portugal Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany Applied Neuroscience Research Group, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia First Department of Neurology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czechia International Clinical Research Centre, St Anne’s University Hospital Brno, Brno, Czechia Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czechia International Clinical Research Centre, Faculty of Medicine, Masaryk University, Brno, Czechia Department of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Texas, 78712, Austin, USA The authors declare no competing interests.
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