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Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats with α-synucleinopathy

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Titel: Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats with α-synucleinopathy
Autoren: Bismark Gatica-Garcia, Michael J. Bannon, Irma Alicia Martínez-Dávila, Luis O. Soto-Rojas, David Reyes-Corona, Lourdes Escobedo, Minerva Maldonado-Berny, ME Gutierrez-Castillo, Armando J. Espadas-Alvarez, Manuel A. Fernandez-Parrilla, Juan U. Mascotte-Cruz, CP Rodríguez-Oviedo, Irais E. Valenzuela-Arzeta, Claudia Luna-Herrera, Francisco E. Lopez-Salas, Jaime Santoyo-Salazar, Daniel Martinez-Fong
Quelle: Neural Regen Res
Neural Regeneration Research, Vol 19, Iss 9, Pp 2057-2067 (2024)
Verlagsinformationen: Medknow, 2023.
Publikationsjahr: 2023
Schlagwörter: 0301 basic medicine, a1 astrocytes, a2 astrocytes, gene therapy, microglia, motor deficits, nanoparticles, neurodegeneration, neuroinflammation, senescence, α-synuclein aggregates, 0303 health sciences, 03 medical and health sciences, Neurology. Diseases of the nervous system, RC346-429, Research Article
Beschreibung: JOURNAL/nrgr/04.03/01300535-202409000-00039/figure1/v/2024-01-30T062302Z/r/image-tiff Parkinsonism by unilateral, intranigral β-sitosterol β-D-glucoside administration in rats is distinguished in that the α-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time, thus replicating several clinical features of Parkinson's disease, a typical α-synucleinopathy. As Nurr1 represses α-synuclein, we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateral β-sitosterol β-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection. This study found that rNurr1-V5 expression but not that of the green fluorescent protein (the negative control) reduced β-sitosterol β-D-glucoside-induced neuropathology. Accordingly, a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum. In addition, tyrosine hydroxylase-positive cells displayed less senescence marker β-galactosidase and more neuron-cytoskeleton marker βIII-tubulin and brain-derived neurotrophic factor. A significant decrease in activated microglia (positive to ionized calcium-binding adaptor molecule 1) and neurotoxic astrocytes (positive to glial fibrillary acidic protein and complement component 3) and increased neurotrophic astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10) also occurred in the substantia nigra. These effects followed the bilateral reduction in α-synuclein aggregates in the nigrostriatal system, improving sensorimotor behavior. Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration (senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells), neuroinflammation (activated microglia, neurotoxic astrocytes), α-synuclein aggregation, and sensorimotor deficits. Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect, supporting its potential clinical use in the treatment of Parkinson's disease.
Publikationsart: Article
Other literature type
Sprache: English
ISSN: 1876-7958
1673-5374
DOI: 10.4103/1673-5374.391190
Zugangs-URL: https://pubmed.ncbi.nlm.nih.gov/38227536
https://doaj.org/article/9b9457524ca44836abbf77cbfbe9fce8
Rights: URL: http://creativecommons.org/licenses/by-nc-sa/4.0/This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Dokumentencode: edsair.doi.dedup.....795e62c4aaaacaeeac0e49b4cf81c93a
Datenbank: OpenAIRE
Beschreibung
Abstract:JOURNAL/nrgr/04.03/01300535-202409000-00039/figure1/v/2024-01-30T062302Z/r/image-tiff Parkinsonism by unilateral, intranigral β-sitosterol β-D-glucoside administration in rats is distinguished in that the α-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time, thus replicating several clinical features of Parkinson's disease, a typical α-synucleinopathy. As Nurr1 represses α-synuclein, we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateral β-sitosterol β-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection. This study found that rNurr1-V5 expression but not that of the green fluorescent protein (the negative control) reduced β-sitosterol β-D-glucoside-induced neuropathology. Accordingly, a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum. In addition, tyrosine hydroxylase-positive cells displayed less senescence marker β-galactosidase and more neuron-cytoskeleton marker βIII-tubulin and brain-derived neurotrophic factor. A significant decrease in activated microglia (positive to ionized calcium-binding adaptor molecule 1) and neurotoxic astrocytes (positive to glial fibrillary acidic protein and complement component 3) and increased neurotrophic astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10) also occurred in the substantia nigra. These effects followed the bilateral reduction in α-synuclein aggregates in the nigrostriatal system, improving sensorimotor behavior. Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration (senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells), neuroinflammation (activated microglia, neurotoxic astrocytes), α-synuclein aggregation, and sensorimotor deficits. Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect, supporting its potential clinical use in the treatment of Parkinson's disease.
ISSN:18767958
16735374
DOI:10.4103/1673-5374.391190