The clinical and pathological differences between synucleinopathies such as Parkinson's disease and multiple system atrophy have been postulated to stem from unique strains of α-synuclein aggregates, akin to what occurs in prion diseases. Here, we demonstrate that inoculation of transgenic mice with different strains of recombinant or brain-derived α-synuclein aggregates produces clinically and pathologically distinct diseases. Strain-specific differences were observed in the signs of neurological illness, time to disease onset, morphology of cerebral α-synuclein deposits, and the conformational properties of the induced aggregates. Moreover, different strains targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting observed between human synucleinopathies. Strain-specific clinical, pathological, and biochemical differences were faithfully maintained upon serial passaging, implying that αsynuclein propagates via prion-like conformational templating. Thus, pathogenic α-synuclein exhibits key hallmarks of prion strains, providing evidence that disease heterogeneity among the synucleinopathies is caused by distinct α-synuclein strains.Parkinson's disease (PD) and related diseases, including dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), are progressive neurodegenerative disorders. The brains of PD, DLB, and MSA patients contain intracellular inclusions composed of aggregated α-synuclein (α-syn). Thus, these diseases are commonly referred to as αsynucleinopathies, or simply synucleinopathies 1 . α-Syn is a 140-amino acid cytoplasmic protein that is found within presynaptic nerve terminals and is involved in the assembly of SNARE complexes 2 . In disease, α-syn polymerizes into insoluble β-sheet-rich protein aggregates that become phosphorylated at residue Ser129 and deposit within the central nervous system 3,4 . α-Syn is believed to play a central pathogenic role in the synucleinopathies since mutation of the gene encoding α-syn causes early-onset PD 5 .There is mounting evidence that α-syn becomes "prion-like" during disease, leading to a progressive cell-to-cell spreading of protein aggregates within the brain 6 . Prions are selfpropagating protein aggregates that cause neurodegenerative disorders such as Creutzfeldt-Jakob disease in humans and scrapie in sheep. Prion replication and spreading is thought to occur via a template-directed refolding mechanism, in which aggregated prion protein (PrP) catalyzes the conformational conversion of properly-folded PrP into additional copies of the misfolded form 7 . Similar to the experimental transmission of prion disease, injection of mice with pre-formed α-syn aggregates induces the aggregation and deposition of α-syn within the brain and, in some instances, accelerates the onset of neurological illness [8][9][10][11][12][13] . The prionlike behavior of α-syn aggregates provides a potential molecular explanation for the progressive nature of PD and related synucleinopathies.The synucleinopathies ar...

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The dendritic cell receptor DC-SIGN mediates pathogen recognition by binding to glycans characteristic of pathogen surfaces, including those found on HIV. Clustering of carbohydrate-binding sites in the receptor tetramer is believed to be critical for targeting of pathogen glycans, but the arrangement of these sites remains poorly understood. Surface force measurements between apposed lipid bilayers displaying the extracellular domain of DC-SIGN and a neoglycolipid bearing an oligosaccharide ligand provide evidence that the receptor is in an extended conformation and that glycan docking is associated with a conformational change that repositions the carbohydrate-recognition domains during ligand binding. The results further show that the lateral mobility of membranebound ligands enhances the engagement of multiple carbohydrate-recognition domains in the receptor oligomer with appropriately spaced ligands. These studies highlight differences between pathogen targeting by DC-SIGN and receptors in which binding sites at fixed spacing bind to simple molecular patterns.adhesion ͉ molecular recognition ͉ pathogen selectivity ͉ multivalent receptors

Compelling evidence indicates that α-synuclein (α-syn) aggregation plays a central role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies. Identification of compounds that inhibit or reverse the aggregation process may thus represent a viable therapeutic strategy against PD and related disorders. Ginseng is a well-known medicinal plant that has been used in East Asia for more than two thousand years to treat several conditions. It is now understood that the pharmacological properties of ginseng can be attributed to its biologically active components, the ginsenosides, which in turn have been shown to have neuroprotective properties. We therefore sought to determine for the first time, the potential of the most frequently used and studied ginsenosides, namely Rg1, Rg3 and Rb1, as anti-amyloidogenic agents. The effect of Rg1, Rg3 and Rb1 on α-syn aggregation and toxicity was determined by an array of biophysical, biochemical and cell-culture-based techniques. Among the screened ginsenosides, only Rb1 was shown to be a potent inhibitor of α-syn fibrillation and toxicity. Additionally, Rb1 exhibited a strong ability to disaggregate preformed fibrils and to inhibit the seeded polymerization of α-syn. Interestingly, Rb1 was found to stabilize soluble non-toxic oligomers with no β-sheet content, that were susceptible to proteinase K digestion, and the binding of Rb1 to those oligomers may represent a potential mechanism of action. Thus, Rb1 could represent the starting point for designing new molecules that could be utilized as drugs for the treatment of PD and related disorders.