Transposable element small and long RNAs in aging brains and implications in Huntington’s and Parkinson’s disease
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Abstract
ABSTRACT Transposable Elements (TEs) are implicated in aging and neurodegenerative disorders, but the impact of brain TE RNA dynamics on these phenomena is not fully understood. Therefore, we quantified TE RNA changes in aging post-mortem human and mouse brains and in the neurodegenerative disorders Huntington’s Disease (HD) and Parkinson’s Disease (PD). We tracked TE small RNAs (smRNAs) expression landscape to assess the relationship to the active processing from TE long RNAs (lnRNAs). Human brain transcriptomes from the BrainSpan Atlas displayed a significant shift of TE smRNA patterns at age 20 years, whereas aging mouse brains lacked any such marked change, despite clear shift in aging-associated mRNA levels. Human frontal cortex displayed pronounced sense TE smRNAs during aging with a negative relationship between the TE smRNAs and lnRNAs indicative of age associated regulatory effects. Our analysis revealed TE smRNAs dysregulation in HD, while PD showed a stronger impact on TE lnRNAs, potentially correlating with the early average age of death for HD relative to PD. Furthermore, TE-silencing factor TRIM28 was down-regulated only in aging human brains, possibly explaining the lack of substantial TE RNA changes in aging mouse brains. Our study suggests brain TE RNAs may serve as novel biomarkers of human brain aging and neurodegenerative disorders.
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ABSTRACT
Transposable Elements (TEs) are implicated in aging and neurodegenerative disorders, but the impact of brain TE RNA dynamics on these phenomena is not fully understood. Therefore, we quantified TE RNA changes in aging post-mortem human and mouse brains and in the neurodegenerative disorders Huntington’s Disease (HD) and Parkinson’s Disease (PD). We tracked TE small RNAs (smRNAs) expression landscape to assess the relationship to the active processing from TE long RNAs (lnRNAs). Human brain transcriptomes from the BrainSpan Atlas displayed a significant shift of TE smRNA patterns at age 20 years, whereas aging mouse brains lacked any such marked change, despite clear shift in aging-associated mRNA levels. Human frontal cortex displayed pronounced sense TE smRNAs during aging with a negative relationship between the TE smRNAs and lnRNAs indicative of age associated regulatory effects. Our analysis revealed TE smRNAs dysregulation in HD, while PD showed a stronger impact on TE lnRNAs, potentially correlating with the early average age of death for HD relative to PD. Furthermore, TE-silencing factor TRIM28 was down-regulated only in aging human brains, possibly explaining the lack of substantial TE RNA changes in aging mouse brains. Our study suggests brain TE RNAs may serve as novel biomarkers of human brain aging and neurodegenerative disorders.
Competing Interest Statement
R.H.M. is a paid Advisory Board member for Rgenta Therapeutics and is on the Scientific Advisory Board with financial interests in Gatehouse Bio Inc.
Data and code availability
All sequencing data produced generated by this study is available on Sequencing Read Archive (SRA) under BioProject PRJNA1113634. See Tables S1 and S2 for specific BioSample and SRA accessions. SRA accessions for publicly available datasets used in this study can be found in Table S1C, S2C. The MSRG pipeline code can be found on the Github repository: https://github.com/laulabbumc/MosquitoSmallRNA
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