Brain deletion of Serf2 shifts amyloid conformation in a mouse model

Abstract

AbstractLoss of protein homeostasis accelerates ageing and contributes to age-related brain diseases like Parkinson’s and Alzheimer’s diseases. Disease-specific proteins become aggregation-prone and form amyloid deposits that characterize disease, but the biological mechanisms driving their transition in cells and tissues are poorly understood. MOAG-4/SERF accelerates aggregation and toxicity of disease-related proteins in worm- and cell models. Whether MOAG-4/SERF affects amyloid pathology in brain, however, has remained unknown. Here we show that brain-specific knockout of SERF2 is viable and shifts aggregation in a mouse model for amyloid-beta aggregation. Without affecting amyloid-beta levels, knockout of SERF2 redirects its assembly into structurally and morphologically distinct amyloid fibrils and deposits. Our results show that SERF modifies the structural outcome of the aggregation process in mammalian brain. With structural polymorphisms recently being associated with disease severity and progression, our results may help to understand the molecular basis for structural diversity and find possibilities for structure-based interventions.HighlightsLoss of SERF2 slows embryonic development and causes perinatal lethalitySERF2 affects proliferation in a cell-autonomous fashionBrain-specific Serf2 knockout does not affect viability or Aβ productionBrain deletion of Serf2 shifts the amyloid conformation of Aβ