Prions and protein aggregates as pathogens, self-propagating structures, biomarkers, and therapeutic targets

Abstract

Many mammalian diseases appear to be caused primarily by the abnormal accumulation of self-propagating assemblies of specific host proteins such as Aβ and tau in Alzheimer’s disease, α-synuclein (aSyn) in Parkinson’s disease, and prion protein (PrP) in classical prion diseases. Most proteinopathies involve a prion-like spreading of the aggregates from localized sites of initiation within the host and, sometimes, between individuals. Often, the pathological assemblies take the form of amyloid fibrils, the cores of many of which have been solved by cryo-electron microscopy, revealing disease-specific, strain-like conformers of the given protein. Amyloids grow via seeded polymerization, a mechanism that is being widely exploited to develop ultrasensitive and specific amplification assays for pathological seeds as biomarkers. Such assays can aid fundamental research, diagnostics, prognostics, and clinical trials for multiple proteinopathies that have been challenging to diagnose and treat. Here, we review the structural biology, transmissibilities, spreading mechanisms, and detection of proteopathic aggregates as well as therapeutic approaches to limiting their accumulation.