To aggregate or not to aggregate – Is it a matter of the ribosome?

Abstract

Neurodegenerative syndromes present as proteinopathies – does ribosomal infidelity contribute to the protein toxicity that is the driving force for neuronal cell loss? Intracellular and extracellular protein aggregates overwhelm the clearance capacity of cells and tissues. Proteins aggregate when hydrophobic residues are exposed. Hydrophobic residues become exposed when proteins are misfolded. Protein misfolding can originate from translational errors at the ribosome. Indeed, the most error‐prone process in gene expression is translation at the ribosome. Recent evidence indicates that manipulating the ribosomal accuracy impacts on the lifespan of model organisms and a reduced translational accuracy is accompanied by neurodegeneration. The first hit in aging‐associated neurodegenerative disease may be the well‐documented decline of cellular buffering capacity by aging. A second hit that impacts on the quality of protein synthesis could be the driving force for the observed loss of proteostasis in neurodegeneration. This hypothesis provides an explanation for the late onset of most neurodegenerative diseases.

Errors in translation act as a “tipping point” leading to the onset of neurodegenerative disease

“…In this issue of BioEssays, an article by Sebastian Iben offers a new hypothesis to address this question. [3] The author's hypothesis states that errors in mRNA translation play a key role in the onset of neurodegenerative disease by serving as a "second hit" that, in combination with an underlying, age-related decline in cellular buffering capacity (the "first hit"), leads to a disruption of proteostasis beyond a critical threshold. This is an intriguing hypothesis that expands current thinking regarding potential causes of age-related neurodegenerative disease by emphasizing a role for translational infidelity, as opposed to other mechanisms such as the failure of chaperone-mediated protein refolding or protein clearance.…”