NAT8L mRNA oxidation is linked to neurodegeneration in multiple sclerosis.

RNA oxidation has been implicated in neurodegeneration, but the underlying mechanism for such effects is unclear. Extensive RNA oxidation occurs within the neurons in multiple sclerosis (MS) brains. Here, we identified selectively oxidized mRNAs in neuronal cells that pertained to neuropathological pathways. N-acetyl aspartate transferase 8 like (NAT8L) is one such transcript, whose translation product enzymatically synthesizes N-acetyl aspartic acid (NAA), a neuronal metabolite important for myelin synthesis. We reasoned that impediment of translation of an oxidized NAT8L mRNA will result in a reduction in its cognate protein, thus lowering the NAA level. This hypothesis is supported by our studies on cells, an animal model, and postmortem human MS brain. Reduced brain NAA level hampers myelin integrity making neuronal axons more susceptible to damage, which contributes to MS neurodegeneration. Overall, this work provides a framework for a mechanistic understanding of the link between RNA oxidation and neurodegeneration.

Rationally designed DNA therapeutics can modulate human TH expression by controlling specific GQ formation in its promoter.

Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the catecholamine (CA) biosynthesis pathway, making TH a molecular target for controlling CA production, specifically dopamine. Dysregulation of dopamine is correlated with neurological diseases such as Parkinson's disease (PD) and post-traumatic stress disorder (PTSD), among others. Previously, we showed that a 49-nucleotide guanine (G)-rich sequence within the human TH promoter adopts two different sets of G-quadruplex (GQ) structures (5'GQ and 3'GQ), where the 5'GQ uses G-stretches I, II, IV, and VI in TH49, which enhances TH transcription, while the 3'GQ utilizes G-stretches II, IV, VI, and VII, which represses transcription. Herein, we demonstrated targeted switching of these GQs to their active state using rationally designed DNA GQ Clips (5'GQ and 3'GQ Clips) to modulate endogenous TH gene expression and dopamine production. As a translational approach, we synthesized a targeted nanoparticle delivery system to effectively deliver the 5'GQ Clip in vivo. We believe this strategy could potentially be an improved approach for controlling dopamine production in a multitude of neurological disorders, including PD.