Involvement of N1-Methyladenosine (m1A) in the mitochondrial ND5 mRNA and the corresponding writer enzyme TRMT10C in Alzheimer's disease
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Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia. Even though the U.S. Food and Drug Administration (FDA) this year approved a new antibody that may moderately decelerate cognitive decline, there is still no treatment that can halt or even reverse the symptoms of AD. Apart from the prime suspects (amyloid β and phosphorylated tau), growing body of evidence suggests mitochondrial dysfunction to be an early and possibly causative event in AD. For the function of mitochondria, Complex I (Cpx I) is of particular importance, as it represents the primary entry point of the electron transport chain required for cellular ATP generation. Although an impairment of Cpx I has been reported multiple times in AD, the underlying mechanism is so far unclear. However, in 2017, a N1-methyladenosine (m1A) modification site has been discovered at position 1374 in the mRNA of ND5, an essential core subunit of Cpx I. Although this m1A1374 site has been unanimously reported, its impact on ND5 protein levels, Cpx I and the mitochondrial respiration is so far unknown. As m1A is known to block Watson-Crick base pairing, this work aimed to investigate whether m1A1374 in the mRNA of ND5 could disrupt the mitochondrial translation of ND5, thus leading to a reduced activity of Cpx I in AD. For this purpose, the tRNA methyltransferase 10 homolog C (TRMT10C) was also examined, as it installs m1A1374 in the mRNA of ND5 (as a so-called writer enzyme). Strikingly, the protein expression of TRMT10C was consistently increased in AD model cells, mice and frontal cortex samples of human AD patients. As revealed by the evaluation of TRMT10C mRNA in single-cell RNA-Seq data from AD patients, this upregulation was cell type-specific for neurons. Besides, m1A1374 methylation was significantly increased in AD model cells, which was determined with a site-specific analysis based on m1A-induced mismatch during reverse transcription and subsequent Illumina sequencing. This result was confirmed in RNA-Seq data generated from the primary visual cortex of AD patients. In line with this, ND5 protein levels were significantly reduced in AD model cells, mice and human AD patients with high Braak stages. The results of this work demonstrate in manifold ways that TRMT10C is involved in the pathology of AD and show for the first time that m1A1374 levels are altered in AD patients. Moreover, the selective overexpression of TRMT10C in HEK cells provides evidence that m1A1374 methylation lowers ND5 protein levels and induces severe mitochondrial deficits. This newly discovered mechanism, along with further research, may provide a basis for the development of new drugs to treat or even cure mitochondrial dysfunction in AD.