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Many neurodegenerative diseases are rooted in the activities of amyloid-like proteins which possess conformations that spread to healthy proteins. These include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). While their clinical manifestations vary, their protein-level mechanisms are remarkably similar. Aberrant monomeric proteins undergo conformational shifts, facilitating aggregation and formation of solid fibrils. However, there is growing evidence that intermediate oligomeric stages are key drivers of neuronal toxicity. Analysis of protein dynamics is complicated by the fact that nucleation and growth of amyloid-like proteins is not a linear pathway. Feedback within this pathway results in exponential acceleration of aggregation, but activities exerted by oligomers and fibrils can alter cellular interactions and the cellular environment as a whole. The resulting cascade of effects likely contributes to the late onset and accelerating progression of amyloid-like protein disorders and the widespread effects they have on the body. In this review we explore the amyloid-like proteins associated with AD, PD, HD and ALS, as well as the common mechanisms of amyloid-like protein nucleation and aggregation. From this, we identify core elements of pathological progression which have been targeted for therapies, and which may become future therapeutic targets., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

While philosophers in ancient times had many ideas for the cause of contagion, the modern study of infective agents began with Fracastoro's 1546 proposal that invisible "spores" spread infectious disease. However, firm categorization of the pathogens of the natural world would need to await a mature germ theory that would not arise for 300 years. In the 19th century, the earliest pathogens described were bacteria and other cellular microbes. By the close of that century, the work of Ivanovsky and Beijerinck introduced the concept of a virus, an infective particle smaller than any known cell. Extending into the early-mid-20th century there was an explosive growth in pathogenic microbiology, with a cellular or viral cause identified for nearly every transmissible disease. A few occult pathogens remained to be discovered, including the infectious proteins (prions) proposed by Prusiner in 1982. This review discusses the prions identified in mammals, yeasts, and other organisms, focusing on the amyloid-based prions. I discuss the essential biochemical properties of these agents and the application of this knowledge to diseases of protein misfolding and aggregation, as well as the utility of yeast as a model organism to study prion and amyloid proteins that affect human and animal health. Further, I summarize the ideas emerging out of these studies that the prion concept may go beyond proteinaceous infectious particles and that prions may be a subset of proteins having general nucleating or seeding functions involved in noninfectious as well as infectious pathogenic protein aggregation., (© 2017 Elsevier Inc. All rights reserved.)