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Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo

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Beel, Sander, Moisse, Matthieu, Damme, Markus, De Muynck, Louis, Robberecht, Wim, Van Den Bosch, Ludo, Saftig, Paul, Van Damme, Philip·2017·Human Molecular Genetics
DOI 10.1093/hmg/ddx162PMC PMC5886064
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Abstract

Loss of function mutations in progranulin (GRN) cause frontotemporal dementia, but how GRN haploinsufficiency causes neuronal dysfunction remains unclear. We previously showed that GRN is neurotrophic in vitro. Here, we used an in vivo axonal outgrowth system and observed a delayed recovery in GRN-/- mice after facial nerve injury. This deficit was rescued by reintroduction of human GRN and relied on its C-terminus and on neuronal GRN production. Transcriptome analysis of the facial motor nucleus post injury identified cathepsin D (CTSD) as the most upregulated gene. In aged GRN-/- cortices, CTSD was also upregulated, but the relative CTSD activity was reduced and improved upon exogenous GRN addition. Moreover, GRN and its C-terminal granulin domain granulinE (GrnE) both stimulated the proteolytic activity of CTSD in vitro. Pull-down experiments confirmed a direct interaction between GRN and CTSD. This interaction was also observed with GrnE and stabilized the CTSD enzyme at different temperatures. Investigating the importance of this interaction for axonal regeneration in vivo we found that, although individually tolerated, a combined reduction of GRN and CTSD synergistically reduced axonal outgrowth. Our data links the neurotrophic effect of GRN and GrnE with a lysosomal chaperone function on CTSD to maintain its proteolytic capacity.

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  • Lysosomal protein constituents such as progranulin and NPC1 interact directly with CTSD, influencing its activity, stability, and conceivably turnover rate.

    “Protein constituents of lysosomes, such as progranulin (Beel et al., 2017) and NPC1 (Liao et al., 2007;Macías-Vidal et al., 2016), also interact directly with CTSD, influencing its activity, stability, and conceivably turnover rate.”

    From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Beel et al., 2017

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Cited by

Sorted by citations

Authors
Beel, S., Moisse, M., Damme, M., De Muynck, L., Robberecht, W., Van Den Bosch, L., Saftig, P., & Van Damme, P.
Affiliations
  • VIB-KU Leuven Center for Brain & Disease Research (BE)
  • Biochemical Institute of the Christian-Albrechts University Kiel, D-24098 Kiel, Germany
  • Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease (LIND), KU Leuven - University of Leuven, B-3000 Leuven, Belgium
  • Universitair Ziekenhuis Leuven (BE)
ORCID
Moisse, Matthieu
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2017-04-26
Volume
26
Issue
15
Pages
2850-2863
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddx162
PMC
PMC5886064
OpenAlex
W2607714873
Cited by
146
References
4
Citations by year
2026: 12 · 2025: 15 · 2024: 8 · 2023: 20 · 2022: 12 · 2021: 23 · 2020: 20 · 2019: 19 · 2018: 11 · 2017: 6
FWCI
10.67
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • EU Joint Programme – Neurodegenerative Disease Research
  • E-Rare
  • European Commission
  • Deutsche Forschungsgemeinschaft (SFB 877)
  • Belgian Federal Science Policy Office (P7/16)
  • Fonds Wetenschappelijk Onderzoek
  • KU Leuven
  • Universiteit Gent
  • Vlaamse regering
  • Fondation pour la Recherche sur Alzheimer
  • FP7 Ideas: European Research Council (340429)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
progranulin, cathepsin D, axon growth, axon regeneration, frontotemporal dementia, facial nerve injury, facial nucleus, neurotrophic factors, proteolytic activity
MeSH terms
Progranulins, Granulins, Animals, Cathepsin D, Facial Nerve, Humans, Mice, Transgenic, Mutation, Molecular Chaperones, Intercellular Signaling Peptides and Proteins, Mice, Frontotemporal Dementia, Haploinsufficiency

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