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Restoration of Adult Neurogenesis by Intranasal Administration of Gangliosides GD3 and GM1 in The Olfactory Bulb of A53T Alpha-Synuclein-Expressing Parkinson’s-Disease Model Mice

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Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting the body and mind of millions of people in the world. As PD progresses, bradykinesia, rigidity, and tremor worsen. These motor symptoms are associated with the neurodegeneration of dopaminergic neurons in the substantia nigra. PD is also associated with non-motor symptoms, including loss of smell (hyposmia), sleep disturbances, depression, anxiety, and cognitive impairment. This broad spectrum of non-motor symptoms is in part due to olfactory and hippocampal dysfunctions. These non-motor functions are suggested to be linked with adult neurogenesis. We have reported that ganglioside GD3 is required to maintain the neural stem cell (NSC) pool in the subventricular zone (SVZ) of the lateral ventricles and the subgranular layer of the dentate gyrus (DG) in the hippocampus. In this study, we used nasal infusion of GD3 to restore impaired neurogenesis in A53T alpha-synuclein-expressing mice (A53T mice). Intriguingly, intranasal GD3 administration rescued the number of bromodeoxyuridine + (BrdU +)/Sox2 + NSCs in the SVZ. Furthermore, the administration of gangliosides GD3 and GM1 increases doublecortin (DCX)-expressing immature neurons in the olfactory bulb, and nasal ganglioside administration recovered the neuronal populations in the periglomerular layer of A53T mice. Given the relevance of decreased ganglioside on olfactory impairment, we discovered that GD3 has an essential role in olfactory functions. Our results demonstrated that intranasal GD3 infusion restored the self-renewal ability of the NSCs, and intranasal GM1 infusion promoted neurogenesis in the adult brain. Using a combination of GD3 and GM1 has the potential to slow down disease progression and rescue dysfunctional neurons in neurodegenerative brains.

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Data availability

The authors agree to share information regarding the conduct of this research and the results obtained from this investigation upon written requests from interested investigators. The authors agree to share any animal models, antibodies, and reagents that are employed in this study upon written requests.

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Acknowledgements

This work was supported by a National Institute of Neurological Disorders and Stroke grant (R01 NS100839 to R.K.Y. and Y.I.) and a Sheffield Memorial Grant of the CSRA Parkinson’s Disease Support Group (to R.K.Y. and Y.I.). We thank Dr. Toshio Ariga and Dr. Dongpei Li for excellent technical support, and Dr. Rhea-Beth Markowitz (Director, Office of Grant Development, Georgia Cancer Center at Augusta University) and Dr. Hannah Soblo (Professional Writing Consultant, Augusta University Center for Writing Excellence) for the editorial excellence and expertise. The authors also wish to acknowledge the excellent infrastructural support of the Department of Neuroscience and Regenerative Medicine (Chair, Dr. Xin-Yun Lu), Medical College of Georgia at Augusta University, which made this investigation possible. This work is dedicated to the memory of Robert K. Yu.

Funding

This work was supported by a National Institute of Neurological Disorders and Stroke grant (R01 NS100839 to R.K.Y. and Y.I.) and a Sheffield Memorial Grant of the CSRA Parkinson’s Disease Support Group (to R.K.Y. and Y.I.).

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Authors and Affiliations

  1. Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Takahiro Fuchigami, Yutaka Itokazu & Robert K. Yu

  2. Movement Disorders Program, Parkinson’s Foundation Center of Excellence, Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    John C. Morgan

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Contributions

Conception and design, T.F., Y.I., J.C.M. and R.K.Y.; Financial support, Y.I. and R.K.Y.; Administrative support, T.F., Y. I. and R.K.Y.; Provision of study material or patients, T.F., Y. I. and R.K.Y.; Collection and/or assembly of data, T.F. and Y.I.; Data analysis and interpretation, T.F. and Y.I.; Manuscript writing, T.F. and Y.I.; Final approval of manuscript, T.F., Y.I., and J.C.M.

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Correspondence to Yutaka Itokazu.

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All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) at Augusta University (AU) according to the National Institutes of Health (NIH) guidelines and performed with the approved animal protocols (references AUP 2009–0240 and 2014–0694).

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The gangliosides nomenclature are based on Svennerholm [1] and IUPAC–IUB [2].

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Fuchigami, T., Itokazu, Y., Morgan, J.C. et al. Restoration of Adult Neurogenesis by Intranasal Administration of Gangliosides GD3 and GM1 in The Olfactory Bulb of A53T Alpha-Synuclein-Expressing Parkinson’s-Disease Model Mice. Mol Neurobiol 60, 3329–3344 (2023). https://doi.org/10.1007/s12035-023-03282-2

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