RNA-binding proteins implicated in neurodegenerative diseases

Abstract

Gene expression is regulated at many levels, including after generation of the primary RNA transcript from DNA but before translation into protein. Such post-translational gene regulation occurs via the action of a multitude of RNA binding proteins and include varied actions from splicing to regulation of association with the translational machinery. Primary evidence that such processes might contribute to disease mechanisms in neurodegenerative disorders comes from the observation of mutations in RNA binding proteins, particularly in diseases in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum and in some forms of ataxia and tremor. The bulk of evidence from recent surveys of the types of RNA species that are affected in these disorders suggests a global deregulation of control rather than a very small number of RNA species, although why some groups of neurons are sensitive to these changes is not well understood. Overall, these data suggest that neurodegeneration can be initiated by mutations in RNA binding proteins and, as a corollary, that neurons are particularly sensitive to loss of control of gene expression at the post-transcriptional level. Such observations have implications not only for understanding the nature of neurodegenerative disorders but also how we might intervene therapeutically in these diseases. WIREs RNA 2017, 8:e1397. doi: 10.1002/wrna.1397 For further resources related to this article, please visit the WIREs website.

Figure 1. Post-transcriptional gene regulation

Key aspects of post-transcriptional gene regulation. Although the central dogma of molecular biology, that DNA makes RNA makes protein (biomolecules are shown in black), is generally true and is useful, there are a variety processing steps (red) that control the flow of information between the key events. Additionally, the control of biological information is compartmentalized within the cell, and here subcellular structures are identified in blue. It should be noted that microRNA (miRNA) species interact with mRNA and can either promote degradation or inhibit translation to protein.

Figure 2. Mutations in RNA binding proteins associated with neurodegeneration

A variety of proteins associated with adult onset neurodegenerative disease contain RNA binding domains. The putative domain structures of proteins that are mutated in neurodegenerative diseases are shown, in alphabetical order. For each protein, RNA binding domains are in green, nuclear localization (L) or exclusion (E) sequences are in blue, Zinc finger domains are in black and amino acid repeats or amino-acid enriched domains are in shades of red and orange. Above each ideogram are examples of specific mutations found in each gene. Additional abbreviations; KH, heterogeneous nuclear ribonucleoprotein K homology; Lsm, Like Sm; Lsm-AD, Lsm associated domain; PAM2, PABP [poly(A)-binding protein] interacting motif; pQ, poly Q (glutamine); RRM, RNA recognition motif; ZNF, zinc finger. It is worth noting that mutations are only rarely found in the RNA binding motifs themselves but rather in the structural domains that surround them.