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

• Published in: Molecular neurobiology Vol. 60; no. 6; pp. 3329 - 3344
• Main Authors: Fuchigami, Takahiro, Itokazu, Yutaka, Morgan, John C., Yu, Robert K.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-06-2023; Springer Nature B.V
• Subjects: Administration, Intranasal; alpha-Synuclein - metabolism; Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Bromodeoxyuridine; Cell Biology; Cell self-renewal; Cognitive ability; Dentate gyrus; Dopamine receptors; Dopaminergic Neurons - metabolism; Doublecortin protein; G(M1) Ganglioside; Gangliosides; Hippocampus; Intranasal administration; Mice; Movement disorders; Neural stem cells; Neurobiology; Neurodegeneration; Neurodegenerative diseases; Neurogenesis; Neurogenesis - physiology; Neurology; Neurosciences; Olfactory bulb; Olfactory Bulb - metabolism; Parkinson Disease; Parkinson's disease; Substantia nigra; Subventricular zone; Synuclein; Tremor; Ventricle (lateral); Ganglioside GM1; A53T alpha-synuclein; Neurogenesis; Ganglioside GD3; Parkinson’s disease; Neural stem cell
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-023-03282-2

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.