Abstract: Human prion-like proteins often correspond to nucleic acid binding proteins, displaying both globular domains and long intrinsically disordered regions (IDRs) (Harrison and Shorter, 2017). Their IDRs are of low complexity and resemble in amino acid composition to the disordered yeast prion domains, being usually enriched in Gln and Asn residues and depleted in hydrophobic and charged residues. Accordingly, these sequence stretches are named prion-like domains (PrLDs). Prion-like proteins can aggregate into amyloid fibrils, which can accommodate incoming protein monomers, propagating thus the polymeric fold, both processes being driven by their PrLDs. Human prion-like proteins are attracting attention because they are found in the insoluble inclusions identified in an increasing number of neurodegenerative diseases (Harrison and Shorter, 2017). Some well-characterized examples are FUS, TDP43, TAF15, EWSR1, TIA1, hnRNPA1, and hnRNPA2 proteins. Importantly, mutations in the genes that encode for these polypeptides are connected with degenerative diseases, such as amyotrophic lateral sclerosis, frontotemporal dementia or multisystem proteinopathy. A significant proportion of these mutations map in the PrLD of the prion-like protein, and often they result in their accelerated aggregation, both in vitro and in vivo. These proteins shuttle between the nucleus and the cytoplasm and are involved in the formation of membraneless organelles, like stress granules, through liquid-liquid phase separation (LLPS) (Boeynaems et al., 2018). Their aggregation typically occurs after protein mislocalization to the cytoplasm, where they form the insoluble inclusions observed in patients. It has been hypothesized that LLPS, which creates a high local protein density, is the first step towards a liquid-to-solid state transition that initiates aggregation. Membraneless organelles are highly dynamic in order to sense environmental changes and generate adequate adaptative responses. This property obeys to the fact that prion-like proteins phase separate via transient and weak non-covalent interactions. Nevertheless, genetic mutations can strengthen LLPS interactions, increasing the kinetic barrier for dissociation, leading to the population of an irreversible aberrant state, which resolves into the aggregates observed in the above-described diseases. Thus, mutations in these prion-like proteins have been suggested to result in a gain of toxic function phenotype similar to the one occurring in the brain of patients with neurodegenerative diseases like Alzheimer’s and Parkinson’s diseases