Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin

J Cell Biol. 2015 Sep 14;210(6):991-1002. doi: 10.1083/jcb.201502029.


Mutations in the progranulin (PGRN) gene have been linked to two distinct neurodegenerative diseases, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests a critical role of PGRN in lysosomes. However, how PGRN is trafficked to lysosomes is still not clear. Here we report a novel pathway for lysosomal delivery of PGRN. We found that prosaposin (PSAP) interacts with PGRN and facilitates its lysosomal targeting in both biosynthetic and endocytic pathways via the cation-independent mannose 6-phosphate receptor and low density lipoprotein receptor-related protein 1. PSAP deficiency in mice leads to severe PGRN trafficking defects and a drastic increase in serum PGRN levels. We further showed that this PSAP pathway is independent of, but complementary to, the previously identified PGRN lysosomal trafficking mediated by sortilin. Collectively, our results provide new understanding on PGRN trafficking and shed light on the molecular mechanisms behind FTLD and NCL caused by PGRN mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / deficiency
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Endocytosis
  • Genotype
  • Granulins
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / deficiency
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lysosomes / metabolism*
  • Lysosomes / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Degeneration
  • Neurons / metabolism*
  • Neurons / pathology
  • Phenotype
  • Progranulins
  • Protein Binding
  • Protein Transport
  • Receptor, IGF Type 2 / metabolism
  • Receptors, LDL / metabolism
  • Saposins / deficiency
  • Saposins / genetics
  • Saposins / metabolism*
  • Transfection
  • Tumor Suppressor Proteins / metabolism


  • Adaptor Proteins, Vesicular Transport
  • GRN protein, human
  • Granulins
  • Grn protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • PSAP protein, human
  • Progranulins
  • Psap protein, mouse
  • Receptor, IGF Type 2
  • Receptors, LDL
  • Saposins
  • Tumor Suppressor Proteins
  • cation-dependent mannose-6-phosphate receptor
  • sortilin