Small non-coding RNAs in neurological-neurodegenerative disorders
M. Bañez-Coronel, M. Friedländer, B. Kagerbauer, E. Lizano, E. Mateu, E. Marti
We have characterized small non-coding RNAs (sncRNAs), in brain samples from individuals at different evolutionary stages of Parkinson’s disease (PD) and control age-matched individuals, using illumina- based high-throughput sequencing. We have sequenced small-RNAs of the amygdala of individuals with diagnosed PD (Braak stages 4-5), Individuals at Braak stages 2-3 and control individuals without major histopathological lesionas and no neurological signs. The individuals at Braak stages 2-3 are considered pre-motor or pre-clinical cases of PD, showing incipient Lewy body (LB) lesions at certain brain areas, although they did not report neurological abnormalities.
Our analyses suggest a strong sncRNA expres- sion deregulation at pre-motor cases, including miRNAs and sncRNAs derived from tRNAs, snoRNAs and lncRNAs. Importantly, around 50 % of the differentially-expressed sncRNAs (miRNAs and others) were also deregulated in the motor cases, suggesting that the expression of sncRNAs is an early pheno- mena that may underlie epigenetic gene expression perturbations. Importantly, the majority of sncRNAs, specially miRNAs, were downregulated in both in pre-motor and motor cases. Preliminary analyses sn- cRNA sequencing data of the frontal cortex of PD cases (Brak stages 4-5) that show few LB pathology revealed a considerable number of overlapping deregulated miRNAs, further indicating that deregulation is not strictly linked to the degree of histopathological lesions.
The group is also studying the role of small non-coding RNAs in neurodegeneration associated to triplet repeat expansion diseases such as Huntington’s disease (HD) and fragile X-associated tremor ataxia syndrome (FXTAS). The group is evaluating the role of small CAG and CGG repeated RNA (sCAG and sCGG) in generating toxic effects in neurons. During this year we have been evaluating the mechanisms associated to the protective effects of anti-sCAG molecules in HD. Intra-striatal injection of anti-sCAG into R6/2 HD mouse model resulted in an improvement of the motor deficits. We are currently investiga- ting the mechanisms associated to the improvement of the motor deficits, including evaluation of early transcriptional changes. Transcriptomic modulation by sCAG is also being evaluated in a neuronal cell model.
Finally, we have been involved in the evaluation of the transcriptional perturbations associated to CGG expansion in FMR1 5’-UTR in FXTAS patients.