Abstract
BackgroundMethylation of mitochondrial tRNAs (mt-tRNA) at the 9th position (“p9 site”) is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression.MethodsMitochondrial p9 methylation was inferred from multi-allelic calls in RNA-seq data. Gene-based association studies were performed in FUMA. Correlations between nuclear gene expression and p9 methylation were tested using Spearman’s rho. Fisher’s Exact test was used in PANTHER and IPA to test for overrepresentation and enrichment of biological processes and pathways in the top nuclear genes correlated with p9 methylation.ResultsVariable methylation was observed at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Certain nuclear encoded genes were identified as significantly associated with p9 methylation. Expression of 5300 nuclear encoded genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. Overrepresentation and enrichment testing using the top transcripts revealed enrichment for a number of molecular processes, terms and pathways including many of which that were mitochondrial-related.ConclusionWith mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer’s disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus.
Highlights
Methylation of mitochondrial tRNAs at the 9th position (“p9 site”) is known to impact translational efficiency and downstream mitochondrial function; direct assessment of mitochondrial RNA (mt-RNA) methylation is challenging
We observed comparable posttranscriptional mitochondrial tRNAs (mt-tRNA) hypermethylation and nuclear gene expression profiles in the cerebellum of Alzheimer’s disease and progressive supranuclear palsy patients. Technical limitations in this analysis do not allow us to conclude on methylation status of the mature tRNA pool, the results here are likely indicative of molecular similarities underlying the mitochondrial dysfunction already known to occur within the cerebellum of individuals diagnosed with either of these tauopathies
A basal level of p9 methylation is required for proper tRNA folding and stability [7] and the degree of methylation at p9 sites has been shown by other groups to have low inter-individual variability [43]
Summary
Methylation of mitochondrial tRNAs (mt-tRNA) at the 9th position (“p9 site”) is known to impact translational efficiency and downstream mitochondrial function; direct assessment of mt-RNA methylation is challenging. Though the genetic etiology of neurodegeneration is highly heterogeneous, there is an extensive literature implicating mitochondrial dysfunction as a common and early factor in the pathophysiology of a number of neurodegenerative diseases [1]. As post-transcriptional processing can alter mitochondrial protein synthesis, aberrant modifications to mitochondrial tRNAs (mt-tRNA) may contribute to the mitochondrial dysfunction underlying neurodegeneration and other age-related pathologies. Mitochondria contain their own 16,569 base pair genome consisting of 13 mRNA genes encoding electron transport chain subunits and 2 rRNA genes, which are ‘punctuated’ by 22 tRNA genes [3]. Knockdown of key processing molecules such as MRPP1 has been shown to lead to accumulation of improperly processed tRNAs resulting in decreased mitochondrial protein synthesis [10]
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