Acta Neuropathologica

, Volume 136, Issue 1, pp 1–17 | Cite as

The lysosomal function of progranulin, a guardian against neurodegeneration

  • Daniel H. Paushter
  • Huan Du
  • Tuancheng Feng
  • Fenghua Hu


Progranulin (PGRN), encoded by the GRN gene in humans, is a secreted growth factor implicated in a multitude of processes ranging from regulation of inflammation to wound healing and tumorigenesis. The clinical importance of PGRN became especially evident in 2006, when heterozygous mutations in the GRN gene, resulting in haploinsufficiency, were found to be one of the main causes of frontotemporal lobar degeneration (FTLD). FTLD is a clinically heterogenous disease that results in the progressive atrophy of the frontal and temporal lobes of the brain. Despite significant research, the exact function of PGRN and its mechanistic relationship to FTLD remain unclear. However, growing evidence suggests a role for PGRN in the lysosome—most striking being that homozygous GRN mutation leads to neuronal ceroid lipofuscinosis, a lysosomal storage disease. Since this discovery, several links between PGRN and the lysosome have been established, including the existence of two independent lysosomal trafficking pathways, intralysosomal processing of PGRN into discrete functional peptides, and direct and indirect regulation of lysosomal hydrolases. Here, we summarize the cellular functions of PGRN, its roles in the nervous system, and its link to multiple neurodegenerative diseases, with a particular focus dedicated to recent lysosome-related mechanistic developments.


Frontotemporal lobar degeneration (FTLD) Neuronal ceroid lipofuscinosis (NCL) Lysosomal storage disease (LSD) Alzheimer’s disease (AD) Progranulin TMEM106B Sortilin Prosaposin GBA Cathepsin Lysosome Microglia Inflammation 



3'-untranslated region



Alzheimer’s disease


A disintegrin and metalloproteinase with thrombospondin motifs 7


Amyotrophic lateral sclerosis


Chromosome 9 open reading frame 72


Charged multivesicular body protein 2B


Cation-independent mannose-6-phosphate receptor


Ceroid lipofuscinosis, neuronal 11


Cysteine protease of protease-inhibitor complex


Cathepsin D


Cathepsin L


EPH receptor A2


Endosomal sorting complexes required for transport-III


Frontotemporal dementia


Frontotemporal lobar degeneration


FTLD with fused in sarcoma protein-positive inclusions


FTLD with GRN mutation


FTLD with tau-positive inclusions


FTLD with TAR DNA-binding protein 43-positive inclusions




Gaucher disease


Granulin–epithelin precursor


Genome-wide association study


Heat shock protein 70


Induced pluripotent stem cell


Lysosome membrane protein 2


Low-density lipoprotein receptor-related protein 1


Lysosomal storage disease


Microtubule-associated protein 6


Microtubule-associated protein tau


Neuronal ceroid lipofuscinosis




PC cell-derived growth factor


Parkinson’s disease






Progressive nonfluent aphasia


Primary progressive aphasia


Nerve growth factor precursor






Semantic dementia


Sequestosome 1


Single-nucleotide polymorphism


TANK-binding kinase 1


TAR DNA-binding protein 43


Transcription factor EB


Trans-Golgi network


Tumor necrosis factor


Triggering receptor expressed on myeloid cells 2


Valosin-containing protein



This work is supported by funding to F.H. from NINDS (R01NS088448, R01NS095954).


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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular BiologyCornell UniversityIthacaUSA

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