The aggregation of proteins into oligomers and amyloid fibrils is characteristic of several neurodegenerative diseases, including Parkinson disease (PD). In PD, the process of aggregation of α-synuclein (α-syn) from monomers, via oligomeric intermediates, into amyloid fibrils is considered the disease-causative toxic mechanism. We developed α-syn mutants that promote oligomer or fibril formation and tested the toxicity of these mutants by using a rat lentivirus system to investigate loss of dopaminergic neurons in the substantia nigra. The most severe dopaminergic loss in the substantia nigra is observed in animals with the α-syn variants that form oligomers (i.e., E57K and E35K), whereas the α-syn variants that form fibrils very quickly are less toxic. We show that α-syn oligomers are toxic in vivo and that α-syn oligomers might interact with and potentially disrupt membranes.

Plethora of Secretory Amyloids: Protein aggregation and the formation of amyloids are associated with several dozen pathological conditions in humans, including Alzheimer's disease, Parkinson's disease, and type II diabetes. In addition, a few functional amyloid systems are known: the prions of fungi, the bacterial protein curli, the protein of chorion of the eggshell of silkworm, and the amyloid protein Pmel-17 involved in mammalian skin pigmentation. Now Maji et al. (p. 328 , published online 18 June) propose that endocrine hormone peptides and proteins are stored in an amyloid-like state in secretory granules. Thus, the amyloid fold may represent a fundamental, ancient, and evolutionarily conserved protein structural motif that is capable of performing a wide variety of functions contributing to normal cell and tissue physiology.

The aggregation of proteins into amyloid fibrils is associated with several neurodegenerative diseases. In Parkinson's disease it is believed that the aggregation of α-synuclein (α-syn) from monomers by intermediates into amyloid fibrils is the toxic disease-causative mechanism. Here, we studied the structure of α-syn in its amyloid state by using various biophysical approaches. Quenched hydrogen/deuterium exchange NMR spectroscopy identified five β-strands within the fibril core comprising residues 35–96 and solid-state NMR data from amyloid fibrils comprising the fibril core residues 30–110 confirmed the presence of β-sheet secondary structure. The data suggest that β1-strand interacts with β2, β2 with β3, β3 with β4, and β4 with β5. High-resolution cryoelectron microscopy revealed the protofilament boundaries of ≈2 × 3.5 nm. Based on the combination of these data and published structural studies, a fold of α-syn in the fibrils is proposed and discussed.