N1-methylation of adenosine (m1A) in ND5 mRNA leads to complex I dysfunction in Alzheimer's disease.

One mechanism of particular interest to regulate mRNA fate post-transcriptionally is mRNA modification. Especially the extent of m1A mRNA methylation is highly discussed due to methodological differences. However, one single m1A site in mitochondrial ND5 mRNA was unanimously reported by different groups. ND5 is a subunit of complex I of the respiratory chain. It is considered essential for the coupling of oxidation and proton transport. Here we demonstrate that this m1A site might be involved in the pathophysiology of Alzheimer's disease (AD). One of the pathological hallmarks of this neurodegenerative disease is mitochondrial dysfunction, mainly induced by Amyloid ß (Aß). Aß mainly disturbs functions of complex I and IV of the respiratory chain. However, the molecular mechanism of complex I dysfunction is still not fully understood. We found enhanced m1A methylation of ND5 mRNA in an AD cell model as well as in AD patients. Formation of this m1A methylation is catalyzed by increased TRMT10C protein levels, leading to translation repression of ND5. As a consequence, here demonstrated for the first time, TRMT10C induced m1A methylation of ND5 mRNA leads to mitochondrial dysfunction. Our findings suggest that this newly identified mechanism might be involved in Aß-induced mitochondrial dysfunction.

A New Bacterial Adenosine-Derived Nucleoside as an Example of RNA Modification Damage.

The fields of RNA modification and RNA damage both exhibit a plethora of non-canonical nucleoside structures. While RNA modifications have evolved to improve RNA function, the term RNA damage implies detrimental effects. Based on stable isotope labelling and mass spectrometry, we report the identification and characterisation of 2-methylthio-1,N6-ethenoadenosine (ms2 ϵA), which is related to 1,N6-ethenoadenine, a lesion resulting from exposure of nucleic acids to alkylating chemicals in vivo. In contrast, a sophisticated isoprene labelling scheme revealed that ms2 ϵA biogenesis involves cleavage of a prenyl moiety in the known transfer RNA (tRNA) modification 2-methylthio-N6-isopentenyladenosine (ms2 i6 A). The relative abundance of ms2 ϵA in tRNAs from translating ribosomes suggests reduced function in comparison to its parent RNA modification, establishing the nature of the new structure in a newly perceived overlap of the two previously separate fields, namely an RNA modification damage.

Thermodynamic characterization of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its acyclic analogs.

Cyclization of small molecules is a widely applied strategy in drug design for ligand optimization to improve affinity, as it eliminates the putative need for structural preorganization of the ligand before binding, or to improve pharmacokinetic properties. In this work, we provide a deeper insight into the binding thermodynamics of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its linear analogs. Characterization of the thermodynamic binding profiles by isothermal titration calorimetry experiments revealed an unfavorable entropy of the macrocycle compared to the open linear reference ligands. Molecular dynamic simulations and X-ray crystal structure analysis indicated only minor benefits from macrocyclization to fixate a favorable conformation, while linear ligands retained some flexibility even in the protein-bound complex structure, possibly explaining the initially surprising effect of a higher entropic penalty for the macrocyclic ligand.