The seeds of its regulation: natural antisense transcripts as single-gene control switches in neurodegenerative disorders

Debomoy K Lahiri; Bryan Maloney; Ruizhi Wang; Fletcher A White; Kumar Sambamurti; Nigel H Greig; Scott E Counts

doi:10.1016/j.arr.2024.102336

The seeds of its regulation: natural antisense transcripts as single-gene control switches in neurodegenerative disorders

Ageing Res Rev. 2024 May 11:102336. doi: 10.1016/j.arr.2024.102336. Online ahead of print.

Authors

Debomoy K Lahiri¹, Bryan Maloney², Ruizhi Wang³, Fletcher A White⁴, Kumar Sambamurti⁵, Nigel H Greig⁶, Scott E Counts⁷

Affiliations

¹ Departments of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA; Departments of Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Departments of Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: dlahiri@iupui.edu.
² Departments of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA; Departments of Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA.
³ Departments of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Departments of Anesthesia, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
⁶ Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
⁷ Departments of Translational Neuroscience and Family Medicine, Michigan State University, Grand Rapids, MI, USA.

PMID: 38740308
DOI: 10.1016/j.arr.2024.102336

Abstract

Several proteins play critical roles in vulnerability or resistance to neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and frontotemporal dementia (FTD). Regulation of these proteins is critical to maintaining healthy neurohomeostasis. In addition to transcription factors regulating gene transcription and microRNAs regulating mRNA translation, natural antisense transcripts (NATs) regulate mRNA levels, splicing, and translation. NATs' roles are significant in regulating key protein-coding genes associated with neurodegenerative disorders. Elucidating the functions of these NATs could prove useful in treating or preventing diseases. NAT activity is not restricted to mRNA translation; it can also regulate DNA (de)methylation and other gene expression steps. NATs are noncoding RNAs (ncRNAs) encoded by DNA sequences overlapping the pertinent protein genes. These NATs have complex structures, including introns and exons, and therefore bind their target genes, precursor mRNAs (pre-mRNAs), and mature RNAs. They can occur at the 5'- or 3'-ends of a mRNA-coding sequence or internally to a parent gene. NATs can downregulate translation, e.g., microtubule-associated protein tau (MAPT) antisense-1 gene (MAPT-AS1), or upregulate translation, e.g., β-Amyloid site Cleaving Enzyme 1 (BACE1) antisense gene (BACE1-AS). Regulation of NATs can parallel pathogenesis, wherein a "pathogenic" NAT (e.g., BACE1-AS) is upregulated under pathogenic conditions, while a "protective" NAT (e.g., MAPT-AS1) is downregulated under pathogenic conditions. As a relatively underexplored endogenous control mechanism of protein expression, NATs may present novel mechanistic targets to prevent or ameliorate aging-related disorders.

Keywords: Alzheimer's disease; gene expression; gene regulation; natural antisense; short RNA.