α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease

Autor: Isabel Lastres-Becker, Alberto Rábano, Antonio Cuadrado, Nadia G. Innamorato, Ayse Ulusoy, Deniz Kirik, Gurdal Sahin
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Parkinson's disease
Gene Expression
environment and public health
chemistry.chemical_compound
Mice
0302 clinical medicine
genetics [Parkinson Disease]
Gene expression
immunology [alpha-Synuclein]
Genetics (clinical)
Cells
Cultured
Neurons
Mice
Knockout
0303 health sciences
Microglia
Cell Death
Dopaminergic
Parkinson Disease
General Medicine
3. Good health
medicine.anatomical_structure
genetics [alpha-Synuclein]
alpha-Synuclein
immunology [NF-E2-Related Factor 2]
physiopathology [Parkinson Disease]
medicine.symptom
Medical Genetics
Nicotinamide adenine dinucleotide phosphate
NF-E2-Related Factor 2
Mice
Transgenic
Biology
Proinflammatory cytokine
03 medical and health sciences
genetics [Heme Oxygenase-1]
immunology [Heme Oxygenase-1]
immunology [Parkinson Disease]
ddc:570
deficiency [NF-E2-Related Factor 2]
Genetics
medicine
Animals
Humans
Molecular Biology
Neuroinflammation
030304 developmental biology
medicine.disease
pathology [Parkinson Disease]
Disease Models
Animal
nervous system
chemistry
Gliosis
chemistry [alpha-Synuclein]
Immunology
cytology [Neurons]
Cancer research
immunology [Neurons]
030217 neurology & neurosurgery
genetics [NF-E2-Related Factor 2]
Heme Oxygenase-1
Zdroj: Human molecular genetics 21(14), 3173-3192 (2012). doi:10.1093/hmg/dds143
Human Molecular Genetics; Vol 21
Digital.CSIC. Repositorio Institucional del CSIC
instname
Human Molecular Genetics; 21(14), pp 3173-3192 (2012)
ISSN: 0964-6906
DOI: 10.1093/hmg/dds143
Popis: 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. © The Author 2012. Published by Oxford University Press. All rights reserved.
This work was supported by grants SAF2010-172218 [to A.C.] from the Spanish MICINN, “Bolsa de Investigación L’Oreal-UNESCO 2010” [to I.L.B.], Swedish Research Council (K2009-61-20945-03-1), European Community’s Seventh Framework Programme FP7-HEALTH-2009 under grant agreement no. 241791 (MEFOPA) and from the European Research Council under grant agreement no. ERC-2009-StG 242932 (TreatPD) [to D.K.]. I.L.B. is recipient of a Ramón y Cajal contract (MICINN-RYC) and A.U. is a recipient of European Union Marie Curie Actions Research Training Network Program in Nervous System Repair (MRTN-CT-2003-504636).
Databáze: OpenAIRE
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