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

Lastres-Becker, Isabel; Ulusoy, Ayse LU ; Innamorato, Nadia G.; Sahin, Gurdal LU ; Rabano, Alberto; Kirik, Deniz LU and Cuadrado, Antonio (2012) In Human Molecular Genetics 21(14). p.3173-3192
Abstract
Although -synuclein (-SYN) aggregation is a hallmark of sporadic and familial Parkinsons 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 -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... (More)
Although -synuclein (-SYN) aggregation is a hallmark of sporadic and familial Parkinsons 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 -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 -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-1 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 -SYN and Nrf2 deficiency cooperate on protein aggregation, neuroinflammation and neuronal death and provides a bifactorial animal model to study early-stage PD. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
21
issue
14
pages
3173 - 3192
publisher
Oxford University Press
external identifiers
  • wos:000305822700007
  • scopus:84864023667
ISSN
0964-6906
DOI
10.1093/hmg/dds143
language
English
LU publication?
yes
id
913e3762-314e-470f-8cb1-252f7d549d93 (old id 3001380)
date added to LUP
2012-09-03 07:19:58
date last changed
2017-10-22 03:06:46
@article{913e3762-314e-470f-8cb1-252f7d549d93,
  abstract     = {Although -synuclein (-SYN) aggregation is a hallmark of sporadic and familial Parkinsons 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 -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 -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-1 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 -SYN and Nrf2 deficiency cooperate on protein aggregation, neuroinflammation and neuronal death and provides a bifactorial animal model to study early-stage PD.},
  author       = {Lastres-Becker, Isabel and Ulusoy, Ayse and Innamorato, Nadia G. and Sahin, Gurdal and Rabano, Alberto and Kirik, Deniz and Cuadrado, Antonio},
  issn         = {0964-6906},
  language     = {eng},
  number       = {14},
  pages        = {3173--3192},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {alpha-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease},
  url          = {http://dx.doi.org/10.1093/hmg/dds143},
  volume       = {21},
  year         = {2012},
}