MANF is essential for astrocyte survival in the monkey brain

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a non-canonical neurotrophic factor and an endoplasmic reticulum (ER) stress protein. While MANF deficiency causes neurodevelopmental issues in humans, its absence in mice does not manifest clear neurological phenotypes, highlighting species-specific roles. Through CRISPR/Cas9 genome editing, we knocked down MANF expressions in the brains of adult mice and cynomolgus monkeys. Our study revealed that reducing MANF levels does not impact neuronal survival in either mice or monkeys, but it specifically affects astrocytes in monkeys. Transcriptomic analysis unveiled reduced leukemia inhibitory factor (LIF) levels following MANF depletion in primary monkey astrocyte cultures, leading to diminished pro-survival STAT3 signaling.Bolstering LIF signaling exhibited protective effects against apoptosis. Given the critical role of astrocytes in brain development and function, our findings underscore the primate-specific function of MANF in astrocyte survival and propose LIF as a promising therapeutic avenue for addressing neurodevelopmental disorders in MANF-deficient individuals.