Protein translation errors stemming from ribosome stalling are increasingly recognized as a pervasive phenomenon in organisms undergoing disease progression and the aging process. These errors are hypothesized to be a key initiating factor in the destabilization of the proteome observed in these physiological states. The Ribosome-Associated Quality Control (RQC) pathway plays a critical role as a cellular surveillance mechanism dedicated to the resolution of these stalled ribosomes and the management of the aberrant polypeptide chains they produce.
Research conducted in Drosophila melanogaster has uncovered significant genetic interactions between Clbn, a gene encoding a core component of the RQC pathway, and CTSD, the fruit fly homolog of the human CLN10 gene. Specifically, loss-of-function in Clbn was found to worsen the phenotypic manifestations associated with CTSD mutations. These exacerbated phenotypes included a marked reduction in lifespan, a noticeable impairment of motor abilities, and the development of neurological dysfunction, highlighting a functional link between these two genes.
Beyond its interaction with CTSD, Clbn appears to be indispensable for the maintenance of normal aging processes within Drosophila tissues. Notably, Clbn influences the primary protein degradation pathway that is activated in response to abnormal proteins, and this choice of pathway differs significantly between young and old physiological conditions. This age-dependent shift in the selection of protein degradation pathways, regulated in part by Clbn, may be a critical factor underlying the pathogenic mechanisms associated with CLN10-related neuropathologies in humans. The observed genetic interactions in Drosophila provide a valuable model system for further investigating the complex interplay between ribosome quality control, protein degradation, and the development of age-related neurodegenerative disorders.