Adeno-Associated virus-based approaches for mitochondrial diseases: advances and challenges.

Schizophrenia is a severe, chronic neurodevelopmental disorder characterized by positive symptoms (hallucinations, delusions), negative symptoms (avolition, anhedonia, affective flattening), and cognitive deficits. Its lifetime prevalence is approximately 1% worldwide []. One of the key pathological findings is the reduction of dendritic spines in pyramidal neurons of the prefrontal cortex, which is linked to symptoms such as impaired sensorimotor gating [–]. Despite extensive research, the biological mechanisms driving schizophrenia remain unclear. Epidemiological evidence has firmly implicated prenatal malnutrition in schizophrenia risk. In the Dutch famine of World War II, many pregnant women were exposed to acute starvation. Cohort studies revealed that male offspring of mothers exposed during the first trimester had nearly a twofold increased risk of schizophrenia [–]. This tragic “natural experiment” provided strong support for the Developmental Origins of Health and Disease (DOHaD) hypothesis, which posits that early-life adversity predisposes to adult disease through epigenetic programming [–]. DNA methylation is the most well-studied mechanism linking prenatal nutrition to long-term disease risk. Early embryogenesis is marked by global waves of DNA demethylation and de novo methylation [–]. Nutritional stress during this critical period may disrupt one-carbon metabolism (involving folate, methionine, and B vitamins). This disruption can reduce the availability of S-adenosylmethionine (SAM), the universal methyl donor []. Such limitation of methyl donor supply can interfere with the proper establishment of DNA methylation patterns [, ]. These alterations can persist across the lifespan and even across generations, reshaping gene expression without altering the DNA sequence. Indeed, genome-wide studies of individuals prenatally exposed to famine have identified differential DNA methylation, particularly among those exposed in the periconceptional period [–].