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

Abstract

Background: Methylation 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. Methods: Mitochondrial 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. Results: Variable 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. 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

“…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 ( Silzer et al 2020 ). This modification may be representative of high metabolic activity in cumulus cells that is not present in oocytes.…”

“…Studies that have used ultra-deep sequencing of mitochondrial RNA (mtRNA) have identified remarkable levels of sequence variation within individuals, as well as sites that show consistent patterns of post-transcriptional modification ( Hodgkinson et al 2014 , Bar-Yaacov et al 2016 ). Expression of nuclear-encoded genes potentially drives such modifications ( Hodgkinson et al 2014 , Silzer et al 2020 ). To our knowledge, there are no published RNA-seq data on oocyte mitochondrial transcripts.…”

Targeted Mitochondrial Epigenetics: A New Direction in Alzheimer’s Disease Treatment

“…Loss of m1A methyltransferase leads to a more harmful AD phenotype [ 75 ]. Variable hypermethylation affecting the translation of downstream mitochondrial proteins was observed at the ninth position (p9) of mt-tRNA in cerebellar tissue after death in elderly AD patients, and a significant correlation between nuclear gene expression and p9 methylation was found [ 76 ]. mt-tRNA methylation may affect the expression of nuclear genes through retrograde signaling, but the mechanism behind this is unclear [ 77 , 78 ].…”

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 …”