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Whereas many cases of neurodegenerative disease feature the abnormal accumulation of protein, an abundance of recent literature highlights loss of RNA homeostasis as a ubiquitous and central feature of pathological states. In some diseases expanded repeats have been identified in non-coding regions of disease-associated transcripts, calling into question the relevance of protein in the disease mechanism. We review the literature in support of a hypothesis that intrinsically disordered proteins (proteins that lack a stable three dimensional conformation) are particularly sensitive to an age-related decline in maintenance of protein homeostasis. The potential consequences for structurally disordered RNA-binding proteins are explored, including their aggregation into complexes that could be transmitted through a prion-like mechanism. We propose that the spread of ribonucleoprotein complexes through the nervous system could propagate a neuronal error catastrophe at the level of RNA metabolism.

Structural disorder and the loss of RNA homeostasis in aging and neurodegenerative disease