Mesencephalic astrocyte-derived neurotrophic factor (MANF) (MANF)

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an 18 kDa endoplasmic reticulum (ER) resident protein that is secreted in response to ER stress, promoting neuroprotection particularly for dopaminergic neurons in the ventral midbrain. It attenuates the unfolded protein response (UPR) by binding to ERN1/IRE1, reducing ER stress-induced apoptosis, and regulates autophagy and lysosomal function via HLH-30/TFEB signaling to maintain proteostasis. MANF localizes to the ER and Golgi via its RTDL retention signal, which interacts with KDEL receptors, and can be endocytosed after binding sulfatides on target cell membranes. Beyond neuroprotection, it supports neuronal development, survival in ischemia and neurodegeneration models, immune modulation by shifting macrophages to anti-inflammatory phenotypes, and cardioprotection. Its deficiency leads to ER stress susceptibility, dopaminergic neuron loss, diabetes, and protein aggregation, while overexpression extends lifespan and reduces aggregates in animal models. MANF's broad expression and cytoprotective roles position it as a potential therapeutic for ER stress-driven diseases, though no approved drugs directly target it yet.

Other names

Arginine-rich protein (ARP-1)CDNF-related protein