An increasing number of human diseases, that are typically associated with aging, often originate from misfolding and aggregation of well-defined proteins. These include neurodegenerative conditions, such as Alzheimer, Parkinson and prion diseases, frontotemporal dementia, amyotrophic lateral sclerosis, as well as non-neuropathic diseases, such as systemic amyloidosis, type II diabetes and many others. It is also increasingly recognized that protein aggregation is a key process in some types of cancer, such as those associated with p53 mutations. 
In this Seminar, the main pathways leading a protein to misfold, oligomerize aberrantly and then form large and insoluble aggregates will be shown, along with the mechanisms of protection used by cells to prevent these deleterious events. The main mechanisms through which aging and mutations promote protein aggregation will be discussed. It will then show the recent progress in the field brought by solid-state nuclear magnetic resonance and cryogenic electron microscopy to elucidate the structure of the main protein aggregates that accumulate in pathology, namely amyloid fibrils, and how our community has progressed substantially to the elucidation of their structure and polymorphism, with a resolution down to <3.0 Å. 
I will finally show the main contributions of our lab to elucidate the effect of mutations on amyloid fibril formation, the regions of the sequence determining fibril structure and their associated polymorphism. We will also show how aberrant protein oligomers forming during aggregation or released from mature fibrils cause cell dysfunction and prospective therapeutic strategies to neutralise them.