, 2009). Furthermore, numerous animal studies using toxin-induced models of PD have shown that modulating the inflammatory response can ameliorate neuronal loss (Wang et al., 2005). However, it remains unclear

how these models relate to the slowly progressive neurodegeneration that occurs in patients with idiopathic or familial forms of PD. As PD is associated with an abnormal accumulation of α-synuclein into Lewy bodies, one hypothesis is that misfolded α-synuclein induces an inflammatory response. This could occur either through the release of α-synuclein into the extracellular space, or by direct engulfment of α-synuclein as microglia participate in the regulation of synaptic membranes (Zhang et al., 2005). Interestingly, histological studies in PD patients grafted with nondiseased R428 clinical trial fetal dopaminergic neurons reveal that Lewy bodies emerge in transplanted neurons (Kordower et al., 2008a and Li et al., 2008). Specifically, only patients with a robust perigraft inflammatory response were observed to have Lewy bodies in grafted neurons,

while grafted neurons survived without Lewy pathology in patients lacking evidence of perigraft microglia activation (Mendez et al., 2008). One parsimonious explanation for these findings is that an immune find more response to the graft facilitates the spread of Lewy body pathology from the host to the graft (Dawson, 2008). If this conjecture is valid, it raises the intriguing possibility that disease-associated misfolded or aggregate proteins such as α-synuclein can acquire prion-like properties and that prion-like propagation of diseased proteins from cell to

cell may be facilitated by exposure to an inflammatory milieu. The prevailing view and that neurodegenerative pathology is driven by protein misfolding and generation of toxic conformers originated in the late 1990s with the observation that disease-causing proteins such as α-synuclein and polyglutamine share common amyloidogenic properties and cascades characteristic of Alzheimer’s and prion diseases. A common theme of misfolded protein toxicity thus links prion diseases with Alzheimer’s disease, Parkinson’s disease, ALS, polyglutamine diseases, and tauopathies. However, prion diseases have been viewed as unique among the neurodegenerative proteinopathies, since prions have the capacity for cell-to-cell and organism-to-organism dissemination. The infectivity of prion protein is well established, so much so that in its prion-like state, designated as PrPSc, prion protein can induce nonpathogenic prion protein, PrPc, to undergo a conformational change into the pathogenic PrPsc state (Pan et al., 1993). In this conformational conversion, which can even occur across species barriers in certain cases (e.g.