Abstract
Recent decades of cutting-edge research have unraveled abnormal nucleotide repeat expansions that manifest themselves in the form of neuronal or neuromuscular disorders. Depending on the location of the repeat expansion, which may be either in the coding or in the noncoding region, cells may succumb to death owing to protein toxicity or RNA toxicity or even both. This chapter highlights the anomalies in the noncoding regions, that is, in FXTAS, DM1, DM2, SCA8, and C9orf72ALS/FTD. Repeat expansion in the noncoding region poses multitudes of cellular pathogenicities. The repeat expanded transcript forms secondary structures, which may either confer neuroprotection or result in neurodegeneration. The expanded RNA can act as a molecular sink and titrate away RNA-binding proteins. The depleted pool of RNA-binding proteins hinders with important functions like splicing and RNA processing. Alternatively, some repeat expanded RNAs can form into small RNAs (sRNAs) that may result silencing of target-complementary sequences. In addition, expanded repeats may be aberrantly translated to produce short peptides despite lacking a start codon, by a phenomenon known as repeat associated non-ATG (RAN) translation. Faithful animal models and high-resolution molecular techniques have led to a paradigm shift in our understanding of repeat expansion disorders. Toxicity owing to RNA expansion has far more overwhelming implications than that previously perceived. It underlies even classical polyQ diseases like SCA3. For identifying the pathogenic involvement of coding as well as the non coding RNAs as the critical underlying mechanisms of expansion disorders, Drosophila melanogaster can be credited immensely. It has not only helped unravel the underlying molecular mechanisms of the disease pathogenicity but has also provided us with novel avenues for therapeutic interventions. In this chapter, we have highlighted knowledge obtained from the Drosophila model in understanding the complex noncoding repeat expansion-associated neurodegenerative disorders. Five major disorders caused by expansion in the non-coding region have been discussed elaborately in this chapter. The readers will be enlightened about the contribution of this tiny fly, not only as an unerring in vivo model but also as a robust tool and platform for therapeutic interventions.
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Das, R., Chakraborty, M., Mukherjee, A., Mutsuddi, M. (2019). Understanding the Pathogenicity of Noncoding RNA Expansion-Associated Neurodegenerative Disorders. In: Mutsuddi, M., Mukherjee, A. (eds) Insights into Human Neurodegeneration: Lessons Learnt from Drosophila. Springer, Singapore. https://doi.org/10.1007/978-981-13-2218-1_12
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