Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.

Background N6-methyladenosine (m6A) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain. Results We show that m6A modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, m6A shows a distinct tissue-specific methylation profile, which is most pronounced in the hypothalamus. Tissue-specific methylation is associated with an increase in mRNA expression and is associated with tissue-specific developmental processes. During the aging process, we observe significantly more m6A sites as age increases, in both mouse and human. We show a high level of overlap between mouse and human; however, humans at both young and old ages consistently show more m6A sites compared to mice. Differential m6A sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These m6A sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased m6A methylation in a mouse model of Alzheimer’s disease, which is correlated with reduced protein levels. Conclusions Our results suggest that m6A exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, m6A controls protein levels of key genes involved in Alzheimer’s disease-associated pathways, suggesting that m6A plays an important role in aging and neurodegenerative disease.

Highlights d miR-451 is the most abundant miRNA in erythrocytes and is clustered with miR-144 d miR-144 targets Dicer in a negative-feedback loop during erythropoiesis d miR-451 is refractory to the loss of Dicer due to its Ago2dependent processing d miR-144 influences the processing of miR-451 in trans

The pervasive transcription of genomes into long noncoding RNAs has been amply demonstrated in recent years and garnered much attention. Similarly, emerging 'epitranscriptomics' research has shown that chemically modified nucleosides, thought to be largely the domain of tRNAs and other infrastructural RNAs, are far more widespread and can exert unexpected influence on RNA utilization. Both areas are characterized by the often-ephemeral nature of the subject matter in that few individual examples have been fully assessed for their molecular or cellular function, and effects might often be subtle and cumulative. Here we review available information at the intersection of these two exciting areas of biology, by focusing on four RNA modifications that have been mapped transcriptome-wide: 5-methylcytidine, N6-methyladenosine, pseudouridine as well as adenosine to inosine (A-to-I) editing, and their incidence and function in long noncoding RNAs. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa.