Neurodegeneration Exploring Commonalities Across Diseases: Workshop Summary (2013) / Chapter Skim
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6 Errors in RNA
6 Errors in RNA
Pages 57-64
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From page 57... ...
They are dispropor tionately expressed within the central nervous system, where they have roles in gene expression, development, neural network plasticity and connectivity, stress response, and brain aging. Base pair mutations to ncRNA can have widespread biological effects in light of ncRNA's unusually broad and interconnected gene and cellular regulatory roles, and they are implicated in neurodegenerative disease.
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From page 58... ...
Unlike protein aggregation, which is well known as a pathological feature common to many neurodegenerative diseases, the recognition that there are errors in RNA in a series of neurodegenerative diseases is currently emerging, and these errors may not be regarded as primary pathogenic mechanisms in some conditions, such as Alzheimer's disease or Parkinson's disease. RNA Gain of Function Mechanisms in Neurogenerative Disease: Microsatellite Expansion Disorders Microsatellite expansion disorders are ones in which mutations are repeating sequences of base pairs of DNA.
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From page 59... ...
was shown to promote exon inclusion in H-ras mRNA, through indirect binding to structural regulatory elements located on the downstream intron.
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From page 60... ...
In transgenic animals with myotonic dystrophy, mis-splicing of a chloride channel causes myotonia, and mis-splicing of the insulin receptor is thought to lead to insulin resistance that is associated with the disease, noted Ranum. In the process of studying myotonic dystrophy and the neurodegenerative disease spinocerebellar ataxia type 8, which features a CAG expansion (Koob et al., 1999)
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From page 61... ...
Thus it is not surprising that ncRNAs have been implicated in neurodegenerative diseases, noted Mark Mehler of the Albert Einstein College of Medicine. In one example, a non-coding antisense RNA against β-secretase (BACE1-AS)
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From page 62... ...
The ASOs that ISIS develops work in one of two ways: by a Ribonuclease H method that cleaves and degrades the RNA once the ASO binds to the target sequence, or by a mechanism that modulates splicing. The latter approach is being used to treat spinal muscular atrophy (SMA)
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From page 63... ...
Rigo reported that ISIS has developed clinical experience with SMA and ALS, while myotonic dystrophy type I and familial dysautonomia are currently at the preclinical stage. They are also pursuing Huntington's disease by reducing the expression of the huntingtin protein with an ASO that operates by the ribonuclease H approach.
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From page 64... ...
(Rigo) • Establish a clear clinical development path to drug approval because there are no currently approved disease-modifying drugs for many neurodegenerative diseases.
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