Amyloid accelerator polyphosphate fits as the mystery density in α-synuclein fibrils.

Aberrant aggregation of α-Synuclein is the pathological hallmark of a set of neurodegenerative diseases termed synucleinopathies. Recent advances in cryo-electron microscopy have led to the structural determination of the first synucleinopathy-derived α-Synuclein fibrils, which contain a non-proteinaceous, "mystery density" at the core of the protofilaments, hypothesized to be highly negatively charged. Guided by previous studies that demonstrated that polyphosphate (polyP), a universally conserved polyanion, significantly accelerates α-Synuclein fibril formation, we conducted blind docking and molecular dynamics simulation experiments to model the polyP binding site in α-Synuclein fibrils.

Cellular oxidants and the proteostasis network: balance between activation and destruction.

Loss of protein homeostasis (proteostasis) is a common hallmark of aging and age-associated diseases. Considered as the guardian of proteostasis, the proteostasis network (PN) acts to preserve the functionality of proteins during their lifetime. However, its activity declines with age, leading to disease manifestation.

Redox heterogeneity in mouse embryonic stem cells individualizes cell fate decisions.

Pluripotent embryonic stem cells (ESCs) can develop into any cell type in the body. Yet, the regulatory mechanisms that govern cell fate decisions during embryogenesis remain largely unknown. We now demonstrate that mouse ESCs (mESCs) display large natural variations in mitochondrial reactive oxygen species (mitoROS) levels that individualize their nuclear redox state, H3K4me3 landscape, and cell fate.