Olangir r hcrase a elcitr published: 29 June 2011 doi: 10.3389/fnins.2011.00080 α-Synuclein alters toll-like receptor expression Dawn Béraud1, Margaret Twomey 1, Benjamin Bloom1, Andrew Mittereder1,Vy Ton1, Katherine Neitzke1, Sergey Chasovskikh 2,Timothy R. Mhyre1 and Kathleen A. Maguire-Zeiss1* 1 Interdisciplinary Program in Neuroscience, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA 2 Lombardi Comprehensive Cancer Center; Georgetown University Medical Center, Washington, DC, USA Edited by: Iliya Lefterov, University of Pittsburg, USA Reviewed by: Iliya Lefterov, University of Pittsburg, USA Spaska Angelova Stanilova,Trakia University, Bulgaria Nicholas Fitz, University of Pittsburgh, USA *Correspondence: Kathleen A. Maguire-Zeiss, Department of Neuroscience, Georgetown University Medical Center, NRB EP08, 3970 Reservoir Road NW, Washington, DC 20057, USA. e-mail: km445@georgetown.edu Parkinson’s disease, an age-related neurodegenerative disorder, is characterized by the loss of dopamine neurons in the substantia nigra, the accumulation of α-synuclein in Lewy bodies and neurites, and neuroinflammation. While the exact etiology of sporadic Parkinson’s disease remains elusive, a growing body of evidence suggests that misfolded α-synuclein promotes inflammation and oxidative stress resulting in neurodegeneration. α-Synuclein has been directly linked to microglial activation in vitro and increased numbers of activated microglia have been reported in an α-synuclein overexpressing mouse model prior to neuronal loss. However, the mechanism by which α-synuclein incites microglial activation has not been fully described. Microglial activation is governed in part, by pattern recognition receptors that detect foreign material and additionally recognize changes in homeostatic cellular conditions. Upon proinflammatory pathway initiation, activated microglia contribute to oxidative stress through release of cytokines, nitric oxide, and other reactive oxygen species, which may adversely impact adjacent neurons. Here we show that microglia are directly activated by α-synuclein in a classical activation pathway that includes alterations in the expression of toll-like receptors. These data suggest that α-synuclein can act as a danger-associated molecular pattern. Keywords: microglial activation, pattern recognition receptors, DAMP, inflammation, Parkinson’s disease Icudortn Ino Parkinson’s disease is the second most common neurodegenera- tive disorder, affecting approximately five million people world- wide. Sporadic as well as familial forms of this disease are typified by the loss of substantia nigra pars compacta (SNpc) dopamine neurons, dystrophic projections to the striatum, increased oxida- tion of proteins, lipids and DNA, increased numbers of activated microglia, and intracytoplasmic proteinaceous inclusions in the surviving SNpc dopamine neurons, called Lewy bodies (Duvoisin, 1992; Forno, 1996). One major component of Lewy bodies is fibril- lar α-synuclein, a conformation purported to be toxic to neurons (Spillantini et al., 1997; Giasson et al., 1999; Masliah et al., 2000; Lee et al., 2001; Song et al., 2004; Periquet et al., 2007; Parihar et al., 2008; Feng et al., 2010). In addition to its presence in Lewy bodies, α-synuclein is further implicated in Parkinson’s disease since point mutations and overexpression of the α-synuclein gene, SNCA, are associated with familial forms of this disorder (Polymeropoulos et al., 1996, 1997; Kruger et al., 1998; Singleton et al., 2003, 2004). Moreover, genome-wide association studies (GWAS) have linked SNCA polymorphisms with an increased risk for developing spo- radic Parkinson’s disease (Satake et al., 2009; Simon-Sanchez et al., 2009; Hamza et al., 2010). While the normal function of α-synuclein is not completely understood, genetic and pathological evidence suggests that Parkinson’s disease pathogenesis is closely linked with a toxic gain-of-function of misfolded α-synuclein. Whereas native α-synuclein maintains a random coil structure, this protein exhibits a propensity to misfold into protofibrils and higher- order oligomers following changes in pH and ionic strength, increases in molecular crowding, and interactions with lipid membranes as well as secondary modification such as dopamine adduction, nitrosylation, and phosphorylation (Conway et al., 1998, 2000, 2001; Hashimoto et al., 1999; Kowall et al., 2000; Vila et al., 2000; Perrin et al., 2001; Volles et al., 2001; Ding et al., 2002; Shtilerman et al., 2002; Volles and Lansbury, 2002; Sharon et al., 2003; Fink, 2006; Tsigelny et al., 2008b). Multiple lines of evidence suggest that the pathological role of α-synuclein is linked to this ability to misfold and self-assemble into higher-order structures. In cell culture models, α-synuclein-induced cell death has been associated with the formation of oligomeric α-synuclein, increased cell membrane conductance, mitochondrial, lysosomal and proteasomal dysfunction, and microglial activation (Biasini et al., 2004; Zhang et al., 2005; Reynolds et al., 2008; Su et al., 2008, 2009; Xilouri et al., 2009; Feng et al., 2010). One consequence of these synuclein-driven perturbations is an overall increase in oxi- dative stress which can result from neuronal production of reactive oxygen species (ROS), decreased antioxidant responses as well as ROS emanating from surrounding activated microglia (Hsu et al., 2000; Parihar et al., 2008, 2009). Importantly, studies using α-synuclein transgenic models also support that α-synuclein is associated with the aforementioned cellular changes, resulting in neuronal dysfunc- tion and degeneration, microglial activation, and increased oxidative stress (Feany and Bender, 2000; He et al., 2001; Dawson et al., 2002; Su et al., 2008; Kim et al., 2011). It is not surprising that Parkinson’s disease patients, most of whom have already exhibited a reduction in dopamine content due to presynaptic terminal loss, demonstrate an over six-fold increase in activated microglia compared to control patients (Ouchi et al., 2005, 2009; Bartels and Leenders, 2007). While these immune sur- veillance cells phagocytose cell debris emanating from dying cells and dystrophic neurites, the evidence that microglia are activated in mouse, rat, and non-human primate models of Parkinson’s www.frontiersin.org June 2011 | Volume 5 | Article 80 | 1