Lysosomal processing of progranulin

Mutations resulting in progranulin (PGRN) haploinsufficiency cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. PGRN is localized to the lysosome and important for proper lysosome function. However, the metabolism of PGRN in t...

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Bibliographic Details
Published in:Molecular neurodegeneration 2017-08, Vol.12 (1), p.62-62, Article 62
Main Authors: Zhou, Xiaolai, Paushter, Daniel H, Feng, Tuancheng, Sun, Lirong, Reinheckel, Thomas, Hu, Fenghua
Format: Article
Language:English
Subjects:
Animals
Cathepsins - metabolism
Development and progression
Disease Models, Animal
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Frontotemporal Lobar Degeneration - genetics
Frontotemporal Lobar Degeneration - metabolism
Gene mutation
Genetic aspects
Haploinsufficiency - genetics
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - metabolism
Lysosomes - metabolism
Mice, Knockout
Mutation - genetics
Nervous system diseases
Physiological aspects
Short Report
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Summary:Mutations resulting in progranulin (PGRN) haploinsufficiency cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. PGRN is localized to the lysosome and important for proper lysosome function. However, the metabolism of PGRN in the lysosome is still unclear. Here, we report that PGRN is processed into ~10 kDa peptides intracellularly in multiple cell types and tissues and this processing is dependent on lysosomal activities. PGRN endocytosed from the extracellular space is also processed in a similar manner. We further demonstrated that multiple cathepsins are involved in PGRN processing and cathepsin L cleaves PGRN in vitro. Our data support that PGRN is processed in the lysosome through the actions of cathepsins.
ISSN:1750-1326
1750-1326
DOI:10.1186/s13024-017-0205-9