Abstract
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder typified by tremor, rigidity, akinesia and postural instability due in part to the loss of dopamine within the nigrostriatal system. The pathologic features of this disorder include the loss of substantia nigra dopamine neurons and attendant striatal terminals, the presence of large protein-rich neuronal inclusions containing fibrillar α-synuclein and increased numbers of activated microglia. Evidence suggests that both misfolded α-synuclein and oxidative stress play an important role in the pathogenesis of sporadic PD. Here we review evidence that α-synuclein activates glia inducing inflammation and that Nrf2-directed phase-II antioxidant enzymes play an important role in PD. We also provide new evidence that the expression of antioxidant enzymes regulated in part by Nrf2 is increased in a mouse model of α-synuclein overexpression. We show that misfolded α-synuclein directly activates microglia inducing the production and release of the proinflammatory cytokine, TNF-α, and increasing antioxidant enzyme expression. Importantly, we demonstrate that the precise structure of α-synuclein is important for induction of this proinflammatory pathway. This complex α-synuclein-directed glial response highlights the importance of protein misfolding, oxidative stress and inflammation in PD and represents a potential locus for the development of novel therapeutics focused on induction of the Nrf2-directed antioxidant pathway and inhibition of protein misfolding.
Highlights
In this invited paper we review existing literature, which supports the concept that the Parkinson’s disease (PD) protein α-synuclein plays a role in microglial activation and oxidative stress
We provide new evidence that α-synuclein overexpression induces an antioxidant response and that specific conformers of α-synuclein cause complex morphological and functional microglial responses which involve both proinflammatory molecules and phase-II antioxidant enzymes. We suggest that this multifaceted α-synuclein-directed glial response represents a nexus between protein misfolding, oxidative stress and inflammation providing a potential therapeutic locus to halt the progression of PD
The promoter used to drive Human placental alkaline phosphatase activity (hPLAP) expression in the ARE and synuclein overexpression under the tyrosine hydroxylase promoter (SARE) mice contains 51-base pairs of the rat NAD(P)H: quinone oxidoreductase 1 (NQO1) promoter including the core antioxidant response element (5’-GTGACnnnGC-3’) (Johnson et al 2002). It was previously established by Johnson et al, that cultured neurons and glia from ARE mice express hPLAP when treated with tBHQ, a molecule known to activate ARE through an NF-E2-related factor 2 (Nrf2)-mediated mechanism (Johnson et al 2002; Kraft et al 2004)
Summary
In this invited paper we review existing literature, which supports the concept that the Parkinson’s disease (PD) protein α-synuclein plays a role in microglial activation and oxidative stress. Further evidence for an ongoing inflammatory state in PD comes from studies demonstrating increased levels of proinflammatory molecules (e.g., interleukins, TNF-α, interferon gamma) in patient blood and cerebrospinal fluid (CSF) as well as enhanced numbers of activated CD11bpositive microglia in post-mortem PD brains at autopsy compared with neurologically normal controls (McGeer et al 1988; Barcia et al 2004; El-Agnaf et al 2006; Bartels and Leenders 2007; Brodacki et al 2008; Bartels et al 2010; Shi et al 2011) Taken together, these studies suggest that persistent inflammation and microglial activation are fundamental characteristics of PD the precise initiator, downstream consequences and nature of this activation remain to be fully determined. We discuss the concept that initial microglial activation and enhanced expression of antioxidant enzymes are appropriate cell responses and critical to maintain homeostasis; prolonged microglial activation is harmful and promotes neuronal vulnerability and disease progression
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