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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
Review

Abstract

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.

Keywords

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 

Abbreviations

3′-UTR

3'-untranslated region

Amyloid-β

AD

Alzheimer’s disease

ADAMTS-7

A disintegrin and metalloproteinase with thrombospondin motifs 7

ALS

Amyotrophic lateral sclerosis

C9orf72

Chromosome 9 open reading frame 72

CHMP2B

Charged multivesicular body protein 2B

CI-M6PR

Cation-independent mannose-6-phosphate receptor

CLN11

Ceroid lipofuscinosis, neuronal 11

CPPIC

Cysteine protease of protease-inhibitor complex

CTSD

Cathepsin D

CTSL

Cathepsin L

EphA2

EPH receptor A2

ESCRT-III

Endosomal sorting complexes required for transport-III

FTD

Frontotemporal dementia

FTLD

Frontotemporal lobar degeneration

FTLD-FUS

FTLD with fused in sarcoma protein-positive inclusions

FTLD-GRN

FTLD with GRN mutation

FTLD-TAU

FTLD with tau-positive inclusions

FTLD-TDP

FTLD with TAR DNA-binding protein 43-positive inclusions

GBA

Glucocerebrosidase

GD

Gaucher disease

GEP

Granulin–epithelin precursor

GWAS

Genome-wide association study

Hsp70

Heat shock protein 70

iPSC

Induced pluripotent stem cell

LIMP-2

Lysosome membrane protein 2

LRP1

Low-density lipoprotein receptor-related protein 1

LSD

Lysosomal storage disease

MAP6

Microtubule-associated protein 6

MAPT

Microtubule-associated protein tau

NCL

Neuronal ceroid lipofuscinosis

OPTN

Optineurin

PCDGF

PC cell-derived growth factor

PD

Parkinson’s disease

PEPI

Proepithelin

PGRN

Progranulin

PNFA

Progressive nonfluent aphasia

PPA

Primary progressive aphasia

proNGF

Nerve growth factor precursor

PSAP

Prosaposin

RD21

Responsive-to-desiccation-21

SD

Semantic dementia

SQSTM1

Sequestosome 1

SNP

Single-nucleotide polymorphism

TBK1

TANK-binding kinase 1

TDP-43

TAR DNA-binding protein 43

TFEB

Transcription factor EB

TGN

Trans-Golgi network

TNF

Tumor necrosis factor

Trem2

Triggering receptor expressed on myeloid cells 2

VCP

Valosin-containing protein

Notes

Acknowledgements

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

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Copyright information

© 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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