title: α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease.
abstract: Although α-synuclein (α-SYN) aggregation is a hallmark of sporadic and familial Parkinson's disease (PD), it is not known how it contributes to early events of PD pathogenesis such as oxidative and inflammatory stress. Here, we addressed this question in a new animal model based on stereotaxic delivery of an adeno-associated viral vector (rAAV) for expression of human α-SYN in the ventral midbrain of mice lacking the transcription factor Nrf2 (Nrf2(-/-)). Two months after surgery, Nrf2(-/-) mice exhibited exacerbated degeneration of nigral dopaminergic neurons and increased dystrophic dendrites, reminiscent of Lewy neurites, which correlated with impaired proteasome gene expression and activity. Dopaminergic neuron loss was associated with an increase in neuroinflammation and gliosis that were intensified in Nrf2(-/-) mice. In response to exogenously added α-SYN, Nrf2(-/-) microglia failed to activate the expression of two anti-inflammatory genes, heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate quinone oxidorreductase-1 (NQO1). This impaired Nrf2 response correlated with a shift in the microglial activation profile, towards increased production of proinflammatory markers, IL-6, IL-1β and iNOS and reduced phagocytic capacity of fluorescent beads, and lower messenger RNA levels for TAM receptors Axl and Mer. Postmortem brain tissue samples from patients in early- to middle-stage progression of PD showed increased HO-1 expression in astrocytes and microglia, suggesting an attempt of the diseased brain to compensate these hallmarks of PD through activation of the Nrf2 pathway. This study demonstrates that α-SYN and Nrf2 deficiency cooperate on protein aggregation, neuroinflammation and neuronal death and provides a bifactorial animal model to study early-stage PD.
authors.affiliation: Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Departamento de Bioquímica e Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lastres-Becker
authors.forename: Ayse
authors.initials: A
authors.lastname: Ulusoy
authors.forename: Nadia G
authors.initials: NG
authors.lastname: Innamorato
authors.forename: Gurdal
authors.initials: G
authors.lastname: Sahin
authors.forename: Alberto
authors.initials: A
authors.lastname: Rábano
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
mesh_terms: D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D009474:Neurons / Q000166:cytology* / Q000276:immunology; D010300:Parkinson Disease / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics* / Q000276:immunology
chemical_list: D051267:NF-E2-Related Factor 2; D051844:alpha-Synuclein; D051547:Heme Oxygenase-1