The assembly, processing, and activities of RNA molecules in the cell is a vast topic, even if narrowed to just one part of the body. A short paper can really only briefly summarize the primary areas of interest for researchers involved in the study of neurodegenerative conditions, as is the case here. Transcription of genes to produce RNA molecules is the first step in gene expression, and sweeping changes in gene expression take place with age. A cell is a state machine, its state largely determined by which RNAs and proteins are produced, and in what amount, at any given time. The state of cells determines the function of tissues. Even just the RNA portion of this picture is an enormously complex, incompletely understood soup of molecular interactions.
Neurodegenerative diseases are prevalent age-related diseases. As of 2024, approximately 6.9 million Americans are affected by Alzheimer’s disease (AD), making it the most common neurodegenerative disease, followed by Parkinson’s disease (PD). There are also many less prevalent or rare neurodegenerative diseases such as Huntington’s disease (HD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Though the clinical symptoms of these diseases vary, multiple neurodegenerative diseases share similar underlying pathological mechanisms. The presence of pathological inclusions and causative mutations of RNA-binding proteins (RBPs) is increasingly observed among neurodegenerative diseases. In addition, pathological repeat expansion in multiple diseases, such as ALS, FTD, HD and various types of spinocerebellar ataxia, yields repeat-containing RNAs that could cause neurotoxicity via various mechanisms.
In the post-genomic era, a variety of RNA processing pathways and emerging types of coding and noncoding RNAs have been commonly identified in the disease context, with potential contributions to neurodegeneration. Therapeutic strategies targeting RNA to modulate disease-linked genes have achieved significant success. Here, we focus on RNA-related pathogenic mechanisms in neurodegenerative diseases and updates on RNA-targeting therapeutic approaches that hold great promise. We start with the various RNA processing pathways and provide representative examples of how these pathways are dysregulated in neurodegenerative diseases. Next, we discuss the mechanisms that lead to RBP dysfunction, resulting in dysregulation of RNA processing. Finally, we review the current progress in RNA-targeting therapeutics. The different RNA processing pathways are often interconnected, and most RBPs have multifunctional roles across several RNA processing steps, creating significant interplay among them.
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