Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RNA interference has become the tool of choice to analyse the loss-of-function of individual genes and has been exploited to identify complex regulatory pathways following genomic screening. RNAi has both admirers and detractors, but is undeniably a technique with great potential, which has come a long way in the short time since its discovery. RNAi utilises cellular machinery associated with the processing of naturally occurring micro RNA (miRNAs). Effective use of RNAi requires detailed knowledge of the individual steps and the proteins involved, as well as the similarities and distinctions between miRNA and siRNA pathways. RNAi was originally induced by the introduction of long double stranded RNAs (dsRNAs) into cells in which the RNA was cleaved into short RNAs which effectively interfered with a transcription of cognate mRNA. More recently an introduction of short approximately 22 nucleotide RNA duplexes has become the standard in short-term experiments, but is insufficient for long-term knock-down assays. Long-term expression of siRNAs has been achieved by in vivo transcription from plasmids coding for short hairpin RNAs (shRNAs). The cellular processing of shRNAs shares common features with the biogenesis of naturally occurring miRNA such as cleavage by nuclear RNase Drosha, export from the nucleus, processing by a cytoplasmic RNase Dicer, and incorporation into the RNA-induced silencing complex (RISC). Each step has a crucial influence on the efficiency of RNAi and their consideration should be a part of a standard experimental design. RNAi has moved from a purely experimental technique to the stage of potential clinical applications. The possible use of RNAi in the treatment of spinocerebellar ataxia or amyotrophic lateral sclerosis, with its advantages and pitfalls and possible extensions to other diseases are discussed.
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PMID:Design of shRNAs for RNAi-A lesson from pre-miRNA processing: possible clinical applications. 1632 11

MicroRNAs (miRNAs) are small noncoding RNAs that can act to repress target mRNAs by suppressing translation and/or reducing mRNA stability. Although it is clear that miRNAs and Dicer, an RNase III enzyme that is central to the production of mature miRNAs, have a role in the early development of neurons, their roles in the postmitotic neuron in vivo are largely unknown. To determine the roles of Dicer in neurons, we ablated Dicer in dopaminoceptive neurons. Mice that have lost Dicer in these cells display a range of phenotypes including ataxia, front and hind limb clasping, reduced brain size, and smaller neurons. Surprisingly, dopaminoceptive neurons without Dicer survive over the life of the animal. The lack of profound cell death contrasts with other mouse models in which Dicer has been ablated. These studies highlight the complicated nature of Dicer ablation in the brain and provide a useful mouse model for studying dopaminoceptive neuron function.
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PMID:Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration. 1838 71

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by the expansion of 55-200 CGG repeats in the 5' UTR of FMR1. These expanded CGG repeats are transcribed and accumulate in nuclear RNA aggregates that sequester one or more RNA-binding proteins, thus impairing their functions. Here, we have identified that the double-stranded RNA-binding protein DGCR8 binds to expanded CGG repeats, resulting in the partial sequestration of DGCR8 and its partner, DROSHA, within CGG RNA aggregates. Consequently, the processing of microRNAs (miRNAs) is reduced, resulting in decreased levels of mature miRNAs in neuronal cells expressing expanded CGG repeats and in brain tissue from patients with FXTAS. Finally, overexpression of DGCR8 rescues the neuronal cell death induced by expression of expanded CGG repeats. These results support a model in which a human neurodegenerative disease originates from the alteration, in trans, of the miRNA-processing machinery.
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PMID:Sequestration of DROSHA and DGCR8 by expanded CGG RNA repeats alters microRNA processing in fragile X-associated tremor/ataxia syndrome. 2347 18