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.
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Abbreviations
- 3′-UTR:
-
3'-untranslated region
- Aβ:
-
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
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This work is supported by funding to F.H. from NINDS (R01NS088448, R01NS095954).
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Paushter, D.H., Du, H., Feng, T. et al. The lysosomal function of progranulin, a guardian against neurodegeneration. Acta Neuropathol 136, 1–17 (2018). https://doi.org/10.1007/s00401-018-1861-8
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DOI: https://doi.org/10.1007/s00401-018-1861-8