Transfer RNAs (tRNAs) reach their mature functional form through several steps of processing and modification. Some nucleotide modifications affect the proper folding of tRNAs, and they are crucial in case of the non-canonically structured animal mitochondrial tRNAs, as exemplified by the apparently ubiquitous methylation of purines at position 9. Here, we show that a subcomplex of human mitochondrial RNase P, the endonuclease removing tRNA 5′ extensions, is the methyltransferase responsible for m1G9 and m1A9 formation. The ability of the mitochondrial tRNA:m1R9 methyltransferase to modify both purines is uncommon among nucleic acid modification enzymes. In contrast to all the related methyltransferases, the human mitochondrial enzyme, moreover, requires a short-chain dehydrogenase as a partner protein. Human mitochondrial RNase P, thus, constitutes a multifunctional complex, whose subunits moonlight in cascade: a fatty and amino acid degradation enzyme in tRNA methylation and the methyltransferase, in turn, in tRNA 5′ end processing.
The amyloid precursor protein (APP) and its proteolytic product amyloid beta (A) are associated with both familial and sporadic forms of Alzheimer disease (AD). Aberrant expression and function of microRNAs has been observed in AD. Here, we show that in rat hippocampal neurons cultured in vitro, the down-regulation of Argonaute-2, a key component of the RNA-induced silencing complex, produced an increase in APP levels. Using site-directed mutagenesis, a microRNA responsive element (RE) for miR-101 was identified in the 3-untranslated region (UTR) of APP. The inhibition of endogenous miR-101 increased APP levels, whereas lentiviral-mediated miR-101 overexpression significantly reduced APP and A load in hippocampal neurons. In addition, miR-101 contributed to the regulation of APP in response to the proinflammatory cytokine interleukin-1 (IL-l). Thus, miR-101 is a negative regulator of APP expression and affects the accumulation of A, suggesting a possible role for miR-101 in neuropathological conditions.
Alzheimer disease (AD)2 is the most common form of dementia in aged individuals and is characterized by A plaques, which contain A aggregates and neurofibrillary tangles which consist primarily of aggregated forms of the microtubule-stabilizing protein tau (reviewed in Ref. 1). A peptides are derived from processing of the type I transmembrane protein APP through sequential cleavages by  and ␥ secretase (2-3). The A load during pathology leads to neurological dysfunction. APP is linked to AD; familial AD can be caused by increased expression of APP due to either genomic duplication (4 -5) or regulatory sequence alterations (6). Among the physiological and pathological activators of APP expression (7-8) is the proinflammatory cytokine IL-1 (9). IL-1 is produced in the central nervous system (CNS) in response to damage and influences neuronal function by interacting with the type I IL-1 receptor expressed on neurons (10 -11). IL-1 is overexpressed in AD (12) and has been implicated in initiation and progression of AD pathology (13). In addition, IL-1 promotes APP transcription (14) and translation (9) in various cell types. Transcriptional and post-transcriptional regulation of APP expression has been widely studied and correlated to AD pathogenesis (15-16). Both cell type-specific promoter elements (17) and regulatory elements in the 5Ј-and 3Ј-UTRs of APP mRNA have been identified (9, 18).MicroRNAs are an intriguing class of small noncoding RNA molecules which, in mammals, regulate gene expression primarily by imperfect base pairing with the
SDR5C1 is an amino and fatty acid dehydrogenase/reductase, moonlighting as a component of human mitochondrial RNase P, which is the enzyme removing 5′-extensions of tRNAs, an early and crucial step in tRNA maturation. Moreover, a subcomplex of mitochondrial RNase P catalyzes the N1-methylation of purines at position 9, a modification found in most mitochondrial tRNAs and thought to stabilize their structure. Missense mutations in SDR5C1 cause a disease characterized by progressive neurodegeneration and cardiomyopathy, called HSD10 disease. We have investigated the effect of selected mutations on SDR5C1's functions. We show that pathogenic mutations impair SDR5C1-dependent dehydrogenation, tRNA processing and methylation. Some mutations disrupt the homotetramerization of SDR5C1 and/or impair its interaction with TRMT10C, the methyltransferase subunit of the mitochondrial RNase P complex. We propose that the structural and functional alterations of SDR5C1 impair mitochondrial RNA processing and modification, leading to the mitochondrial dysfunction observed in HSD10 patients.
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