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α-Synuclein pathology and reduced neurogenesis in the olfactory system affect olfaction in a mouse model of Parkinson’s disease

View ORCID ProfileEduardo Martin-Lopez, D.J. Vidyadhara, Teresa Liberia, Sarah J. Meller, Leah E. Harmon, Ryan M. Hsu, Kimberly Han, Betül Yücel, View ORCID ProfileSreeganga S. Chandra, Charles A. Greer
doi: https://doi.org/10.1101/2022.08.19.504562
Eduardo Martin-Lopez
1Department of Neurosurgery, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
3Department of Neuroscience, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
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  • ORCID record for Eduardo Martin-Lopez
D.J. Vidyadhara
2Department of Neurology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
3Department of Neuroscience, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
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Teresa Liberia
1Department of Neurosurgery, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
3Department of Neuroscience, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
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Sarah J. Meller
1Department of Neurosurgery, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
3Department of Neuroscience, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
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Leah E. Harmon
2Department of Neurology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
3Department of Neuroscience, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
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Ryan M. Hsu
1Department of Neurosurgery, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
3Department of Neuroscience, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
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Kimberly Han
1Department of Neurosurgery, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
3Department of Neuroscience, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
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Betül Yücel
2Department of Neurology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
3Department of Neuroscience, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
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Sreeganga S. Chandra
2Department of Neurology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
3Department of Neuroscience, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
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  • For correspondence: charles.greer@yale.edu sreeganga.chandra@yale.edu
Charles A. Greer
1Department of Neurosurgery, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
3Department of Neuroscience, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA
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  • For correspondence: charles.greer@yale.edu sreeganga.chandra@yale.edu
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Abstract

Parkinson’s Disease (PD) is characterized by multiple symptoms including olfactory dysfunction, whose underlying mechanisms remain unclear. Here, we explored pathological changes in the olfactory pathway of transgenic (Tg) mice expressing the human A30P mutant α-synuclein (α-syn) (α-syn-Tg mice) at 6-7 and 12-14 months of age, representing early and late-stages of motor progression, respectively. α-Syn-Tg mice at late stages exhibited olfactory behavioral deficits, which correlated with severe α-syn pathology in projection neurons of the olfactory pathway. In parallel, olfactory bulb (OB) neurogenesis in α-syn-Tg mice was reduced in the OB granule cells at 6-7 months, and OB periglomerular cells at 12-14 months, respectively, both of which could contribute to olfactory dysfunction. Proteomic analyses showed a disruption in endo- and exocytic pathways in the OB during the early stages which appeared exacerbated at the synaptic terminals when the mice developed olfactory deficits at 12-14 months. Our data suggest that, 1) the α-syn-Tg mice recapitulate the olfactory functional deficits seen in PD; 2) olfactory structures exhibit spatiotemporal disparities for vulnerability to α-syn pathology; 3) α-syn pathology is restricted to projection neurons in the olfactory pathway; 4) neurogenesis in adult α-syn-Tg mice is reduced in the OB; and 5) synaptic endo- and exocytosis defects in the OB may further explain olfactory deficits.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 22, 2022.
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α-Synuclein pathology and reduced neurogenesis in the olfactory system affect olfaction in a mouse model of Parkinson’s disease
Eduardo Martin-Lopez, D.J. Vidyadhara, Teresa Liberia, Sarah J. Meller, Leah E. Harmon, Ryan M. Hsu, Kimberly Han, Betül Yücel, Sreeganga S. Chandra, Charles A. Greer
bioRxiv 2022.08.19.504562; doi: https://doi.org/10.1101/2022.08.19.504562
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α-Synuclein pathology and reduced neurogenesis in the olfactory system affect olfaction in a mouse model of Parkinson’s disease
Eduardo Martin-Lopez, D.J. Vidyadhara, Teresa Liberia, Sarah J. Meller, Leah E. Harmon, Ryan M. Hsu, Kimberly Han, Betül Yücel, Sreeganga S. Chandra, Charles A. Greer
bioRxiv 2022.08.19.504562; doi: https://doi.org/10.1101/2022.08.19.504562

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