Murine cathepsin D deficiency is associated with dysmyelination/myelin disruption and accumulation of cholesteryl esters in the brain
Open accessAbstract
J. Neurochem. (2010) 112, 193–203. Cathepsin D (CTSD) deficiencies are fatal neurological diseases that in human infants and in sheep are characterized by extreme loss of neurons and myelin. To date, similar morphological evidence for myelin disruption in CTSD knockout mice has not been reported. Here, we show that CTSD deficiency leads to pronounced myelin changes in the murine brain: myelin‐related proteolipid protein and myelin basic protein were both markedly reduced at postnatal day 24, and the amount of lipids characteristically high in myelin (e.g. plasmalogen‐derived alkenyl chains and glycosphingolipid‐derived 20‐ and 24‐carbon acyl chains) were significantly lowered compared with controls. These changes were accompanied by ultrastructural alterations of myelin, including significant thinning of myelin sheaths. Furthermore, in CTSD knockout brains there was a pronounced accumulation of cholesteryl esters and abnormal levels of proteins related to cholesterol transport, with an increased content of apolipoprotein E and a reduced content of ATP‐binding cassette transporter A1. These results provide evidence for dysmyelination and altered trafficking of cholesterol in brains of CTSD knockout mice, and warrant further studies on the role of lipid metabolism in the pathogenesis of CTSD deficiencies.
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GRN mutations exhibit full penetrance for disease by age 80.
“GRN mutations exhibit full penetrance for disease by age 80.112,113”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [113]
The paper’s Abstract (p. 2) concerns CTSD deficiency and myelin changes in mice, not GRN mutations. Searches for GRN, progranulin, penetrance, and age 80 found no passage addressing the claimed disease penetrance. (LLM, conf=0.76)
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Cites
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
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Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins
Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D., & Mahley, R. W. (1987) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(87)90295-5 · Cited by 693 · see citing works
Tyynelä, J., Sohar, I., Sleat, D. E., Gin, R. M., Donnelly, R. J., Baumann, M., Haltia, M., & Lobel, P. (2000) · The EMBO Journal · doi:10.1093/emboj/19.12.2786 · Cited by 245 · see citing works
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- Boison D. and Stoffel W. (1994) Disruption of the compacted myelin sheath of axons of the central nervous system in proteolipid protein-deficient mice. Proc. Natl Acad. Sci. USA 91 , 11709-11713.
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Vidoni, C., Follo, C., Savino, M., Melone, M. A. B., & Isidoro, C. (2016) · Medicinal Research Reviews · doi:10.1002/med.21394 · Cited by 164 · see citing works
Yang, D.-S., Stavrides, P., Saito, M., Kumar, A., Rodriguez-Navarro, J. A., Pawlik, M., Huo, C., Walkley, S. U., Saito, M., Cuervo, A. M., et al. (2014) · Brain · doi:10.1093/brain/awu278 · Cited by 114 · see citing works
Kaji, S., Maki, T., Kinoshita, H., Uemura, N., Ayaki, T., Kawamoto, Y., Furuta, T., Urushitani, M., Hasegawa, M., Kinoshita, Y., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.12.001 · Cited by 93 · see citing works
Lysosomal Functions in Glia Associated with Neurodegeneration
Kreher, C., Favret, J., Maulik, M., & Shin, D. (2021) · Biomolecules · doi:10.3390/biom11030400 · Cited by 38 · see citing works
Lane-Donovan, C., Paredes, M., & Kao, A. W. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102854 · Cited by 3 · see citing works
- Authors
- Mutka, A., Haapanen, A., Käkelä, R., Lindfors, M., Wright, A. K., Inkinen, T., Hermansson, M., Rokka, A., Corthals, G., Jauhiainen, M., Gillingwater, T. H., Ikonen, E., & Tyynelä, J.
- Affiliations
- University of Helsinki (FI)
- University of Edinburgh (GB)
- Åbo Akademi University (FI)
- Institute for Molecular Medicine Finland (FI)
- ORCID
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2009-12-08
- Volume
- 112
- Issue
- 1
- Pages
- 193-203
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2085661569
- Cited by
- 34
- References
- 3
- Citations by year
- 2026: 1 · 2025: 3 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 3 · 2013: 2 · 2012: 2
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- dysmyelination, myelin damage, cholesteryl ester accumulation, cholesterol transport, proteolipid protein, myelin basic protein, myelin lipid composition, plasmalogens, glycosphingolipids, apolipoprotein E, ABCA1, lipid metabolism, neurodegeneration
- MeSH terms
- Animals, Biological Transport, Active, Brain, Cathepsin D, Cholesterol Esters, Demyelinating Diseases, Mice, Inbred C57BL, Myelin Sheath, Mice, Knockout, Mice
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