Gene defects have been recognized as prominent factors in the etiology and pathogenesis of neurodegenerations.Among 60 neurodegeneration-related mutations in progranulin(PGRN),the mutation in PGRN gene exon 1 introduces a charged amino acid in the hydrophobic core of its signal peptide at residue 9(thus named as PGRN A9D)and results in cytoplasmic missorting.However,the pathogenesis of this mutation remains elusive.To address this issue,we first examined the subcellular distribution of PGRN A9D in human neuronal-like cells(SH-SY5Y).The results showed that PGRN A9D accumulated in cytosolic stress granules.Interestingly,this mutation induced a cellular redistribution of angiogenin(ANG),a stress response factor and neurodegenerative disease-related protein,from nucleus to cytoplasmic stress granules through protein interaction.Further study revealed that the stress granule localization of PGRN A9D was dependent on ANG.Functionally,PGRN A9D abolished the nuclear ANG-mediated biological roles;on the other hand,the relocation of ANG in stress granules activated its cytoprotective stress response program by cleaving tRNAs to tiRNAs(tRNA-derived,stress induced small RNAs),thus promotes PGRN A9D cell survival.Taken together,our results indicate that PGRN A9D retards ANG in the cytoplasm to protect cells from PGRN A9D-induced apoptosis,implying that PGRN and ANG act in concert to regulate the progress of neurodegenerative disease.