Neurodegeneration caused by the translation of nonsense: Does macromolecular misfolding impair the synchrony of gene expression?

Here, it is proposed that the principal event underlying neurodegeneration occurs when cytotoxic, truncated proteins are expressed from normally-untranslated nonsense RNA and pseudogene transcripts. The proximal event occurs when a small fraction of the total pool of gene expression machinery within the cell is disrupted by rare events of macromolecular misfolding during gene expression. Macromolecular misfolding, such as β-sheet formation of protein leading to intracellular aggregation, has been implicated in a number of neurodegerative diseases. As gene expression is a synchronised series of processes from the nucleus to the cytoplasm, should macromolecular misfolding occur in any given component of the gene expression apparatus, co-dependent gene expression processes could become disrupted. For example, should proteins misfold during their own translation, aggregates could accumulate within the translation machinery and disrupt the regulation of upstream gene expression events, such as RNA splicing or Nonsense Mediated Decay. Although only a limited amount of gene expression machinery would be affected by macromolecular misfolding, the resultant loss in fidelity could allow sufficient levels of expression of aberrant proteins from nonsense RNA and pseudogene transcripts to produce cytotoxic effects within the cell over time and ultimately lead to neurodegeneration.