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Published on: August 10, 2018
miRNA analysis reveals novel dysregulated pathways in amyotrophic lateral sclerosis
Junguk Hur1, Ximena Paez-Colasante2, Claudia Figueroa-Romero2,3
1Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Its complex pathogenesis and phenotypic heterogeneity hinder therapeutic development and early diagnosis. Altered RNA metabolism is a recurrent pathophysiologic theme, including distinct microRNA (miRNA) profiles in ALS tissues. We profiled miRNAs in accessible biosamples, including skin fibroblasts and whole blood and compared them in age- and sex-matched healthy controls versus ALS participants with and without repeat expansions to chromosome 9 open reading frame 72 (C9orf72; C9-ALS and nonC9-ALS), the most frequent ALS mutation. We identified unique and shared profiles of differential miRNA (DmiRNA) levels in each C9-ALS and nonC9-ALS tissues versus controls. Fibroblast DmiRNAs were validated by quantitative real-time PCR and their target mRNAs by 5-bromouridine and 5-bromouridine-chase sequencing. We also performed pathway analysis to infer biological meaning, revealing anticipated, tissue-specific pathways and pathways previously linked to ALS, as well as novel pathways that could inform future research directions. Overall, we report a comprehensive study of a miRNA profile dataset from C9-ALS and nonC9-ALS participants across two accessible biosamples, providing evidence of dysregulated miRNAs in ALS and possible targets of interest. Distinct miRNA patterns in accessible tissues may also be leveraged to distinguish ALS participants from healthy controls for earlier diagnosis. Future directions may look at potential correlations of miRNA profiles with clinical parameters.
Insights
Researchers identified distinct microRNA (miRNA) profiles in skin and blood of amyotrophic lateral sclerosis (ALS) patients. These unique miRNA patterns could aid in earlier ALS diagnosis and identify potential therapeutic targets.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex pathogenesis.
- Altered RNA metabolism, including microRNA (miRNA) dysregulation, is implicated in ALS.
- The C9orf72 (C9) repeat expansion is the most common genetic cause of ALS.
Purpose of the Study:
- To profile and compare miRNA expression in accessible biosamples (skin fibroblasts, whole blood) from ALS patients and healthy controls.
- To investigate differences in miRNA profiles between C9orf72-positive (C9-ALS) and C9orf72-negative (nonC9-ALS) individuals.
- To identify potential miRNA targets and pathways involved in ALS pathogenesis.
Main Methods:
- miRNA profiling in skin fibroblasts and whole blood from C9-ALS, nonC9-ALS, and healthy control participants.
- Validation of differentially expressed miRNAs (DmiRNAs) using quantitative real-time PCR.
- Identification of miRNA target mRNAs using 5-bromouridine and 5-bromouridine-chase sequencing.
- Pathway analysis to infer biological significance of observed miRNA changes.
Main Results:
- Identified unique and shared DmiRNA profiles in C9-ALS and nonC9-ALS tissues compared to controls.
- Validated specific DmiRNAs in fibroblasts and identified their mRNA targets.
- Pathway analysis revealed known and novel pathways associated with ALS, suggesting tissue-specific mechanisms.
Conclusions:
- This study provides a comprehensive miRNA profile dataset from ALS patients across two accessible biosamples.
- Dysregulated miRNAs and their potential targets are identified, offering avenues for future research.
- Distinct miRNA patterns in accessible tissues may serve as biomarkers for earlier ALS diagnosis.
