Dysregulation of RNA modification systems in clinical populations with neurocognitive disorders

The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms. Methylation of N6 adenosine (m(6)A) and C5 cytosine (m(5)C) bases occur on mRNAs, tRNA, mt-tRNA, and rRNA species as well as non-coding RNAs. With emerging knowledge of RNA binding proteins that act as writer, reader, and eraser effector proteins, comes a new understanding of physiological processes controlled by these systems. Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain, give rise to different forms of disease. In this review, we discuss accumulating evidence that changes in the m(6)A and m(5)C methylation systems contribute to neurocognitive disorders. Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m(6)A RNA reader protein. Subsequently, familial mutations within the m(6)A writer gene METTL5, m(5)C writer genes NSUN2, NSUN3, NSUN5, and NSUN6, as well as THOC2 and THOC6 that form a protein complex with the m(5)C reader protein ALYREF, were recognized to cause intellectual development disorders. Similarly, differences in expression of the m(5)C writer and reader effector proteins, NSUN6, NSUN7, and ALYREF in brain tissue are indicated in individuals with Alzheimer's disease, individuals with a high neuropathological load or have suffered traumatic brain injury. Likewise, an abundance of m(6)A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases, Alzheimer's disease, and individuals with high cognitive reserve. m(6)A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson's disease tissue, whilst modified RNAs are misplaced within diseased cells, particularly where synapses are located. In parahippocampal brain tissue, m(6)A modification is enriched in transcripts associated with psychiatric disorders including conditions with clear cognitive deficits. These findings indicate a diverse set of molecular mechanisms are influenced by RNA methylation systems that can cause neuronal and synaptic dysfunction underlying neurocognitive disorders. Targeting these RNA modification systems brings new prospects for neural regenerative therapies.