Prions, amyloids, and RNA: Pieces of a puzzle

Abstract

ABSTRACT. Amyloids are protein aggregates consisting of fibrils rich in b-sheets. Growth of amyloid fibrils occurs by the addition of protein molecules to the tip of an aggregate with a concurrent change of a conformation. Thus, amyloids are self-propagating protein conformations. In certain cases these conformations are transmissible / infectious; they are known as prions. Initially, amyloids were discovered as pathological extracellular deposits occurring in different tissues and organs. To date, amyloids and prions have been associated with over 30 incurable diseases in humans and animals. However, a number of recent studies demonstrate that amyloids are also functionally involved in a variety of biological processes, from biofilm formation by bacteria, to long-term memory in animals. Interestingly, amyloid-forming proteins are highly overrepresented among cellular factors engaged in all stages of mRNA life cycle: from transcription and translation, to storage and degradation. Here we review rapidly accumulating data on functional and pathogenic amyloids associated with mRNA processing, and discuss possible significance of prion and amyloid networks in the modulation of key cellular functions.

Changing how we think about infectious diseases

“…If we accept that prion diseases can be produced by self-propagating proteins other than PrP(Scr), then what other diseases might we now investigate as potential prion diseases. Without diverting too far from the subject of this book, we can say that there seems to be a newly described class of diseases characterized by misfolded self-propagating and, under some circumstances, transmissible proteins, which may include the prionopathies, the tauopathies (including Alzheimer disease), and the amyloidoses [31,[35][36][37].…”

An anti-amyloidogenic treatment to specifically block the consolidation of traumatic events in mouse

“…In this line, the discovery of prion-like domains in RNA regulatory proteins that are involved long-term memory [16][17][18][19][20] , unveiled an important mechanism for the stabilization of synaptic growth related to learning [21][22][23][24][25] . Thus, memory storage and underlying synaptic plasticity are mediated by the increase in the concentration of the cytoplasmic polyadenylation element binding protein-3 (CPEB3) and its amyloid conversion 18,26,20 . In vertebrates, CPEB is usually coded by four genes with the first member to be identified being CPEB1, whereas CPEBs 2-4 were described later in mice [27][28][29][30] .…”

Mammalian amyloidogenic proteins promote prion nucleation in yeast

“…Amino acid substitution P101L in mouse PrP (see Fig 7A) corresponds to the human mutation P102L, associated with a heritable prion disease, and is shown to cause disease accompanied by a production of the infectious PrP protein in mice [10]. In contrast, the substitution Q167R is shown to inhibit prion replication in mice [51].…”

“…The region between residues 90 and 119 of PrP, that is known to be essential for the susceptibility to prion infection in mammals [52], is also required for prion nucleation in yeast, while the N-terminal region of PrP (23-89) is dispensable for both (Fig 7). Mutation P101L, associated with heritable prion disease in mammals [10] increased, while mutation Q167R, inhibiting prion replication in mammals decreased PrP-dependent prion nucleation in the yeast assay. Increased prion nucleating ability of the fragments lacking the Cproximal region of PrP (Fig 7) agrees with previous reports linking C-proximal PrP truncations to a heritable neurological disease in humans [53,54,55], and supports a notion that this disease is likely to be prion-like in nature.…”

“…In case of TSEs, the epidemics of "mad cow" disease led to huge losses in the European cattle industry [5]. In addition to disease-related amyloids and prions, some amyloids or amyloid-like protein polymers have been described that are related to biologically positive functions, such as formation of structural fibrous materials (e. g. silks), storage of peptide hormones, scaffolding of covalent polymers (e. g. melanin), and long term memory [9,10].…”