Metabolic functions for molecular chaperones and stress proteins in microcephaly

Neurometabolic disruptions during brain development are central drivers of the structural and functional impairments observed in neurodevelopmental disorders such as microcephaly. While these deficits are often attributed to inherited mutations in metabolic enzymes, emerging evidence highlights the critical role of cellular stress response pathways, particularly those governed by proteostatic machinery, such as molecular chaperones. Although molecular chaperones support brain growth through diverse mechanisms, this review focuses on their role in stabilising metabolic enzymes, preventing their degradation and maintaining proper turnover. Building on this, we explore how stress response pathways operate in the developing brain, and how their dysregulation can impair brain growth. In addition, we examine several microcephaly-associated genes, classically linked to centrosome and mitotic regulation, and discuss their additional roles in modulating many of these stress responses, often intersecting with molecular chaperone systems and purine neurometabolism. Together, these insights underscore the essential protective functions of stress responses in sustaining metabolic processes vital for brain formation and inform potential therapeutic strategies for neurodevelopmental disorders.