Pathogenic chaperone-like RNA induces congophilic aggregates and facilitates neurodegeneration in Drosophila

Abstract

Protein aggregation is a hallmark of many neurodegenerative diseases. RNA chaperones have been suggested to play a role in protein misfolding and aggregation. Noncoding, highly structured RNA recently has been demonstrated to facilitate transformation of recombinant and cellular prion protein into proteinase K-resistant, congophilic, insoluble aggregates and to generate cytotoxic oligomers in vitro. Transgenic Drosophila melanogaster strains were developed to express highly structured RNA under control of a heat shock promoter. Expression of a specific construct strongly perturbed fly behavior, caused significant decline in learning and memory retention of adult males, and was coincident with the formation of intracellular congophilic aggregates in the brain and other tissues of adult and larval stages. Additionally, neuronal cell pathology of adult flies was similar to that observed in human Parkinson's and Alzheimer's disease. This novel model demonstrates that expression of a specific highly structured RNA alone is sufficient to trigger neurodegeneration, possibly through chaperone-like facilitation of protein misfolding and aggregation.

Protein Folding Activity of Ribosomal RNA Is a Selective Target of Two Unrelated Antiprion Drugs

“…In addition, the putative function of the largest rRNA in prion formation/propagation provides mechanistic support for previously unexplained observations in yeast showing the ability of 3 µm plasmid (encoding rRNA) to induce [ psi − ] to [ PSI + ] conversion when introduced into a [ psi − ] strain [46] . Very recently, it has been shown that in Drosophila melanogaster , overexpression of chaperone-like highly structured RNA induces congophilic aggregates and facilitates neurodegeneration [47] , also suggesting that a highly structured RNA alone could be able to trigger neurodegeneration through chaperone-like facilitation of protein misfolding and aggregation.…”

Hsp70 affects memory formation and behaviorally relevant gene expression in Drosophila melanogaster

“…In the latter case, memory was retained for up to 8 h because retrieval of the memory trace is facilitated by the presentation of a fertilized female to the male (Kamyshev et al 1999). The CCSP is used widely for evaluation of basic courtship behavior and learning ability and memory retention in Drosophila (Kuzin et al 2014;Savvateeva-Popova et al 2007;Savvateeva-Popova et al 2008;Godenschwege et al 2004;Redt-Clouet et al 2012;Savvateeva et al 2000;Fedotov et al 2020).…”

Molecular Chaperones and Ubiquitin Proteasome System in Tumor Biogenesis: An Overview

“…However, genetic chaperonopathies have a fairly early onset, while acquired chaperonopathies become exposed in the elderly, occasionally in association with other diseases. It has also been revealed that few prominent groups of chaperone are represented by the 'chaperonopathies by mistake' in which a molecular chaperone may be normal, although takes part in a cascade which indulges disease progression rather than the disease reversal [47]. In such condition, the pathology can be manifested by two types of pathogenic cascades; first the pathway is usual and comprises the participation of one or more chaperones which develops into part of a morbid process; and second the cascade that includes chaperones is not part of a physiological process within the cell, although comes to be potent and functional in morbid cases.…”