Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

Abstract

Background Methylation of mitochondrial tRNAs (mt-tRNA) at the 9 th 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. Results Here we show variable methylation 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. Expression of 5300 genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. The top 100 transcripts were found to be enriched for mitochondrial-related toxicity. Overrepresentation testing using the top 1000 transcripts revealed enrichment for a number of molecular processes and terms including some which were mitochondrial-related. Conclusion With 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.

No evidence for age-related differences in mitochondrial RNA quality in the female germline

“…While this modification appears to be present in 16/24 of cumulus cell samples, and at a high mtRNA heteroplasmy level (average 23%, range 6 -87%), it was only detected in 1/24 oocytes (Figure 3C). In mammalian datasets, P9 methylation is required for correct folding, translational efficiency and downstream mitochondrial function of at least 11 of the mitochondrial tRNAs (14). This modification may be representative of high metabolic activity in cumulus cells that is not present in oocytes.…”

“…Studies that have used ultradeep sequencing of mitochondrial RNA (mtRNA) have identified remarkable levels of sequence variation within individuals, as well as sites that show consistent patterns of posttranscriptional modification (12,13). Expression of nuclear encoded genes potentially drives such modifications (12) (14). To our knowledge there are no published RNA-seq data on oocyte mitochondrial transcripts.…”

Genetic and Epigenetic Constructs of Progressive Supranuclear Palsy

“…76 Furthermore, variable methylation of mitochondrial tRNAs (mt-tRNAs) at 11 site in the ninth position ("p9 site"), which affects the efficiency of the translation as well as downstream mitochondrial function, was observed in PSP patients. 77 "PSP-Look-Alikes": Genetic Conundrum…”

The tRNA regulome in neurodevelopmental and neuropsychiatric disease

“…One of the enzymes mechanistically linked to AD pathology, in both the Drosophila and mouse models, is TRMT10C, which fascinatingly is also significantly decreased in post-mortem dorsolateral prefrontal cortex (DLPFC) of human AD subjects 102 , 103 . Further, another post-mortem study identified hypermethylation of m 1 A9 in the cerebellum of AD subjects 104 , suggesting a brain region-specificity to the mitochondrial tRNA epitranscriptome. It is still unclear how mitochondrial function is altered by the depletion of m 1 A enzymes and hypomethylated mt-tRNAs, but the probable outcome of mitochondrial tRNA loss would likely be on the level of translation efficiency and protein expression, which should be a target of future studies.…”