Non-canonical Microproteins in Neural Development and Neurological Disease: From Molecular Mechanisms to Translational Potential

Neural development is orchestrated by a complex interplay between genetic, epigenetic, and translational mechanisms. Despite the discovery of an increasing number of regulatory factors, a significant “hidden coding dimension” has yet to be fully explored, which is the translation of small open reading frames (sORFs) into traditionally non-coding microproteins. In this review, we synthesized the discoveries and new advances in the functional aspects of sORF-encoded microproteins and systematically summarized their mechanisms in chromatin remodeling, ion homeostasis and phase separation, mitochondrial respiration, neuroimmune crosstalk, and nervous system secretion signaling. This emphasizes the distinction between peptide-dependent functions and RNA-centered regulatory roles, which is often overlooked in early non-classical translation studies. We further evaluate the therapeutic potential of microproteins in neurodevelopmental and neurodegenerative disorders, addressing both biomarker applications and intervention strategies spanning peptide engineering to genomic regulation. By reframing microproteins as versatile molecular fine-tuners rather than translational noise, this review expands the mechanistic understanding of neural development and disease pathogenesis and proposes previously underappreciated potential targets for future basic and clinical investigations. An overview of the role of novel microproteins in brain development and neurological diseases. A summary of the potential roles of novel microproteins in brain development, such as the regulation of cell fate, endoplasmic reticulum (ER) stress, calcium signaling, protein stability, synaptic maturation and plasticity, neural signal transduction, and metabolic regulation.