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

作　　者：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 

机构地区：[1]Departamento de Fisiología,Biofísica y Neurociencias,Centro de Investigación y de Estudios Avanzados,Ciudad de México,México [2]Department of Pharmacology,Wayne State University School of Medicine,Detroit,MI,USA [3]Laboratorio de Patogénesis Molecular,Carrera Médico Cirujano,Facultad de Estudios Superiores Iztacala,Universidad Nacional Autónoma de México,Tlalnepantla de Baz,México [4]Red de Medicina para la Educación y Desarrollo y la Investigación Científica de Iztacala(Red MEDICI),Carrera Médico Cirujano,Facultad de Estudios Superiores Iztacala,Universidad Nacional Autónoma de México,Tlalnepantla de Baz,México [5]Nanoparticle Therapy Institute,Aguascalientes,México [6]Departamento de Biociencias e Ingeniería,Centro Interdisciplinario de Investigaciones y Estudios sobre Medio Ambiente y Desarrollo,Instituto Politécnico Nacional,Ciudad de México,México [7]Escuela Nacional de Medicina y Homeopatía,Instituto Politécnico Nacional,Ciudad de México,México [8]Departamento de Fisiología,Escuela Nacional de Ciencias Biológicas,Instituto Politécnico Nacional,Ciudad de México,México [9]Departamento de Biología Molecular y Biotecnología,Instituto de Investigaciones Biomédicas,Universidad Nacional Autónoma de México,Ciudad de México,México [10]Departamento de Física,Centro de Investigación y de Estudios Avanzados,Ciudad de México,México [11]Programa de Nanociencias y Nanotecnología,Centro de Investigación y de Estudios Avanzados,Ciudad de México,México

出　　处：《Neural Regeneration Research》2024年第9期2057-2067,共11页中国神经再生研究（英文版）

摘　　要：Parkinsonism by unilateral,intranigralβ-sitosterolβ-D-glucoside administration in rats is distinguished in that theα-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time,thus replicating several clinical features of Parkinson’s disease,a typicalα-synucleinopathy.As Nurr1 repressesα-synuclein,we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateralβ-sitosterolβ-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)reducedβ-sitosterolβ-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 markerβ-galactosidase and more neuron-cytoskeleton markerβIII-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 inα-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 facto

关 键 词：A1 astrocytes A2 astrocytes gene therapy microglia motor deficits nanoparticles neurodegeneration neuroinflammation senescence α-synuclein aggregates 

分 类 号：R742.5[医药卫生—神经病学与精神病学]