RNA Therapy for Polyglutamine Neurodegenerative Diseases


The polyglutamine neurodegenerative diseases are caused by the expansion of a CAG repeat, which is translated into an extended polyglutamine tract in the disease‐causing protein. Although arising from a common type of mutation, the mechanisms by which each polyglutamine protein exerts its cellular toxicity are complex. RNA‐based approaches represent promising therapeutic strategies, offering the potential to target and suppress the expression of polyglutamine disease genes in a sequence‐specific manner, upstream of the deleterious effects of the mutant protein. In particular, allele‐specific therapies, which selectively silence the mutant copy of the gene while retaining the wild‐type function, may prove useful in cases where wild‐type gene expression is known to be indispensable. With a variety of RNA technologies currently being developed to target multiple polyglutamine disease genes, the initiation of clinical trials appears imminent. However, the numerous challenges associated with design, dosage and delivery optimisation must be addressed before such therapies can be effectively applied in a clinical setting.

Key Concepts:

  • The elucidation of an effective therapy for any of the inherited polyglutamine repeat disorders may contribute to the alleviation of the global health burden.

  • Because many of the polyglutamine pathogenic mechanisms involve the toxic protein and its intermediates, the most logical therapeutic strategy may be to prevent pathogenesis upstream of these effects.

  • Gene‐based therapies have been heralded as the most promising avenue for therapeutic research, because they may allow for prevention or reversal of disease progression through altering the expression, processing or conformation of the mutant protein.

  • Various RNA‐based targeting strategies for the polyglutamine repeat disorders have been explored, including repeat targeting, allele‐specific silencing, nonallele‐specific silencing and gene knockdown and replacement.

  • Numerous guidelines exist for the design, delivery and dosage of therapeutic effectors.

  • Cell‐based and animal models have contributed significantly towards the testing and improvement of potential therapies, paving the way to clinical application.

Keywords: polyglutamine repeat disorders; neurodegenerative diseases; RNAi; RNA‐based therapies; spinocerebellar ataxia

Figure 1.

Mechanisms of polyQ toxicity. The expansion of CAG trinucleotide repeats within the coding region of several genes results in the expression of proteins containing pathologically expanded polyglutamine (polyQ) tracts. Pathogenesis has largely been attributed to the effects of the mutant protein, although a role for RNA toxicity in the development of disease has also been proposed. The mechanism by which polyQ proteins exert their toxic effects varies according to the protein context, and may include proteolytic cleavage (leading to the production of toxic fragments), impairment of the ubiquitin–proteasome pathway, formation of aggregates of mutant protein (involving the sequestration of wild‐type polyQ protein and other important cellular components such as the transcription factors), dysregulation of transcription, either directly or as a result of aggregate formation, and mitochondrial dysfunction, all of which result in deleterious downstream consequences. Reproduced from Watson and Wood with permission of Cambridge University Press.

Figure 2.

Overview of the endogenous and exogenous RNAi pathways. During the endogenous RNAi process, RNA is transcribed from a (miRNA) or mirtron locus, and folds to form primary miRNA (pri‐miRNA) molecules, or a mirtron lariat. These are processed by the endonuclease Drosha to yield pre‐miRNAs. After exportin 5‐mediated transport into the cytoplasm, the hairpin structure is removed by the Dicer, to yield a short double‐stranded RNA molecule. The RNA‐induced silencing complex (RISC) is directed by the ‘guide’ strand of the RNA complex towards the targeted complementary RNA. A complete base‐pairing to this RNA results in cleavage and degradation of the target mRNA, whereas partial complementarity results in translational repression. Exogenous therapeutic effectors can enter the pathway at various levels, as miRNA mimics, short hairpin RNAs (shRNAs) or short interfering RNAs (siRNAs).



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Further Reading

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Smith, Danielle C, Watson, Lauren M, Greenberg, Jacquie LJ, Wood, Matthew JA, and Scholefield, Janine(Apr 2013) RNA Therapy for Polyglutamine Neurodegenerative Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024909]