Characterization of novel conformation-selective α-synuclein antibodies as potential immunotherapeutic agents for Parkinson's disease.

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases for which there is no disease-modifying treatment. PD and DLB are characterized by aggregation of the synaptic protein α-synuclein, and there is compelling evidence to suggest that progression of these diseases is associated with the trans-cellular spread of pathogenic α-synuclein through the brains of afflicted individuals. Therapies targeting extracellular, pathogenic α-synuclein may therefore hold promise for slowing or halting disease progression.

Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies.

In Lewy body diseases-including Parkinson's disease, without or with dementia, dementia with Lewy bodies, and Alzheimer's disease with Lewy body co-pathology -α-synuclein (α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites . By contrast, in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs) . Here we report that pathological α-Syn in GCIs and Lewy bodies (GCI-α-Syn and LB-α-Syn, respectively) is conformationally and biologically distinct.

Molecular and Biological Compatibility with Host Alpha-Synuclein Influences Fibril Pathogenicity.

The accumulation and propagation of misfolded α-synuclein (α-Syn) is a central feature of Parkinson's disease and other synucleinopathies. Molecular compatibility between a fibrillar seed and its native protein state is a major determinant of amyloid self-replication. We show that cross-seeded aggregation of human (Hu) and mouse (Ms) α-Syn is bidirectionally restricted.

Correction: Comparison of strategies for non-perturbing labeling of α-synuclein to study amyloidogenesis.

Correction for 'Comparison of strategies for non-perturbing labeling of α-synuclein to study amyloidogenesis' by Conor M. Haney, et al., Org.

Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein.

Misfolded α-synuclein amyloid fibrils are the principal components of Lewy bodies and neurites, hallmarks of Parkinson's disease (PD). We present a high-resolution structure of an α-synuclein fibril, in a form that induces robust pathology in primary neuronal culture, determined by solid-state NMR spectroscopy and validated by EM and X-ray fiber diffraction. Over 200 unique long-range distance restraints define a consensus structure with common amyloid features including parallel, in-register β-sheets and hydrophobic-core residues, and with substantial complexity arising from diverse structural features including an intermolecular salt bridge, a glutamine ladder, close backbone interactions involving small residues, and several steric zippers stabilizing a new orthogonal Greek-key topology.

Comparison of strategies for non-perturbing labeling of α-synuclein to study amyloidogenesis.

Characterization of the amyloidogenic Parkinson's disease protein α-synuclein (αS) has proven difficult due to its structural plasticity. Here, we present a number of complementary methods to site-specifically introduce fluorescent probes to examine αS fibril formation and cellular uptake. By using various combinations of conventional Cys modification, amber codon suppression, transferase mediated N-terminal modification, and native chemical ligation, several variants of singly- and doubly-labeled αS were produced.

A C-H oxidation approach for streamlining synthesis of chiral polyoxygenated motifs.

Chiral oxygenated molecules are pervasive in natural products and medicinal agents; however, their chemical syntheses often necessitate numerous, wasteful steps involving functional group and oxidation state manipulations. Herein a strategy for synthesizing a readily diversifiable class of chiral building blocks, allylic alcohols, through sequential asymmetric C-H activation/resolution is evaluated against the state-of-the-art. The C-H oxidation routes' capacity to strategically introduce oxygen into a sequence and thereby minimize non-productive manipulations is demonstrated to effect significant decreases in overall step-count and increases in yield and synthetic flexibility.

Distinct α-synuclein strains differentially promote tau inclusions in neurons.

Many neurodegenerative diseases are characterized by the accumulation of insoluble protein aggregates, including neurofibrillary tangles comprised of tau in Alzheimer's disease and Lewy bodies composed of α-synuclein in Parkinson's disease. Moreover, different pathological proteins frequently codeposit in disease brains. To test whether aggregated α-synuclein can directly cross-seed tau fibrillization, we administered preformed α-synuclein fibrils assembled from recombinant protein to primary neurons and transgenic mice.

Sequential allylic C-H amination/vinylic C-H arylation: a strategy for unnatural amino acid synthesis from α-olefins.

Tandem reaction sequences that selectively convert multiple C-H bonds of abundant hydrocarbon feedstocks to functionalized materials enable rapid buildup of molecular complexity in an economical way. A tandem C-H amination/vinylic C-H arylation reaction sequence is described under Pd(II)/sulfoxide-catalysis that furnishes a wide range of α- and β-homophenylalanine precursors from commodity α-olefins and readily available aryl boronic acids. General routes to enantiopure amino acid esters and densely functionalized homophenylalanine derivatives are demonstrated.