Translation stalling and ribosome collision leading to proteostasis failure: implications for neurodegenerative diseases

Proteostasis denotes a cellular state in which protein synthesis, folding, and degradation are maintained at a homeostatic state such that an intact yet dynamic proteome is preserved. Cellular capacity to preserve proteostasis declines with age, which is assumed to contribute to the pathogenesis of age-related diseases. Proteostasis failure manifested as the formation of aberrant protein aggregates, including the amyloid plaques in Alzheimer's disease (AD), Lewy bodies in Parkinson's disease, and TAR DNA binging protein 43 inclusions in amyotrophic lateral sclerosis (ALS), is a defining feature of neurodegenerative diseases. The root cause of the proteostasis failure and protein aggregation is still enigmatic. Studies in various systems suggest that cellular co-factors play important roles in "seeding" the aforementioned pathogenic protein aggregation. But the molecular nature of the initial seeding activities remains poorly defined. The pathogenic role of the disease-characterizing, macroscopically visible protein aggregates is also uncertain. Several high-profile clinical trials targeting specific protein aggregates are inconclusive and there is no evidence for a clinically relevant therapeutic effect as of now (Mullane and Williams, 2018), suggesting that the key proteostasis-disruptive, disease-causing events remain to be identified. In this perspective, I will discuss recent evidence supporting that faulty translation products resulting from inadequate quality control of translational stalling and ribosome collision during the translation of certain problematic mRNAs can be the root cause of proteostasis failure and may represent novel therapeutic targets for neurodegenerative diseases.