PIWI-interacting RNAs in neurological and neuropsychiatric disorders and potential for clinical development

Neural diseases, including neurological and neuropsychiatric disorders, represent a significant and growing public health burden. While the understanding of the genetic origins of these diseases has advanced considerably in recent years, the underlying causal mechanisms of many sporadic cases remain poorly understood. Recent research highlights the role of noncoding RNAs, such as PIWI-interacting RNAs (piRNAs) and PIWI proteins, in regulating gene expression and maintaining genome stability within neural cells. The piRNA pathway is emerging as a significant regulator of chromatin accessibility and transcriptional homeostasis in nervous system development and plasticity. Concomitantly, a disruption of the piRNA pathway has been associated with neuronal dysfunction and age-associated neuropathologies, underscoring the urgent need to investigate their mechanistic roles in neuronal homeostasis and disease pathogenesis. This review focuses on the emerging functions of the piRNA pathway beyond the gonads, with particular attention given to its potential roles in mammalian nervous system physiology, disease mechanisms, and opportunities for diagnostic and therapeutic development.