Interestingly, the N-terminal RTDL amino acid sequence of MANF, which functions as an ER retention signal, is not required for the in vivo neuroprotective effect of recombinant MANF protein in cerebral ischemia [50], implying that the neuroprotective effect of exogenous MANF may not be directly related to ER homeostasis. The gene discussed is MANF; the disease is brain ischemia.