Nalavade, Rohit: Investigation of the role of microRNAs in Spinocerebellar Ataxia type 3. - Bonn, 2015. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-41730
@phdthesis{handle:20.500.11811/6549,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-41730,
author = {{Rohit Nalavade}},
title = {Investigation of the role of microRNAs in Spinocerebellar Ataxia type 3},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2015,
month = oct,

note = {Spinocerebellar Ataxia Type 3 (SCA3) is an inherited, neurodegenerative disorder belonging to the group of polyglutamine repeat disorders. It is caused by CAG repeat expansions in the ATXN3 gene leading to expanded polyglutamine repeats in the ATXN3 protein. The expanded ATXN3 protein forms intranuclear inclusions in neuronal cells ultimately leading to neuronal death. MicroRNAs are endogenously produced, small, non-coding RNAs that play a role in post-transcriptional regulation of gene expression. MicroRNA mediated regulation of gene expression is associated with several processes such as the development of organisms, maintenance of homeostasis as well as with several human disorders such as cancer and neurodegenerative diseases.
The present study demonstrates the ability of specific microRNAs to target the expression of the proteins ATXN3, MID1 and DNAJB1 which play important roles in the pathogenic mechanisms in SCA3. The microRNAs hsa-miR-32 and hsa-miR-181c were found to target and reduce ATXN3 expression, while hsa-miR-216a-5p, hsa-miR-374a-5p, hsa-miR-542a-3p target and reduce the expression of MID1. Profiling of gene and microRNA expression in iPSC-derived neurons from SCA3 patients and controls revealed that in SCA3 neurons, hsa-miR-370 and hsa-miR-543 that target the expression of the neuroprotective DNAJB1 chaperone are upregulated, while the target DNAJB1 mRNA and protein are downregulated. Similarly, DNAJB1 mRNA level was found to be downregulated in a transgenic SCA3 mouse model suggesting that the miRNA mediated reduction in the neuroprotective DNAJB1 might contribute to the pathogenesis observed in SCA3.
These results demonstrate the two sided role of microRNAs in the pathogenesis of SCA3 by targeting the expression of neurotoxic proteins such as ATXN3, MID1 as well as neuroprotective proteins such as DNAJB1. The findings of this study might contribute towards miRNA based therapeutic strategies such as enhancing miRNA targeting of neurotoxic proteins and preventing miRNA targeting of neuroprotective proteins.},

url = {http://hdl.handle.net/20.500.11811/6549}
}

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