The DOI matches its Crossref record; 73 of the 73 references it cites were found in a registry or an index.
Cholesterol Accumulation Is Associated with Lysosomal Dysfunction and Autophagic Stress in Npc1−/− Mouse Brain
Open accessAbstract
Niemann-Pick type C (NPC) disease is an autosomal recessive disorder caused by mutations of NPC1 and NPC2 genes. Progressive neurodegeneration that accompanies NPC is fatal, but the underlying mechanisms are still poorly understood. In the present study, we characterized the association of autophagic-lysosomal dysfunction with cholesterol accumulation in Npc1(-/-) mice during postnatal development. Brain levels of lysosomal cathepsin D were significantly higher in mutant than in wild-type mice. Increases in cathepsin D occurred first in neurons and later in astrocytes and microglia and were both spatially and temporally associated with intracellular cholesterol accumulation and neurodegeneration. Furthermore, levels of ubiquitinated proteins were higher in endosomal/lysosomal fractions of brains from Npc1(-/-) mice than from wild-type mice. Immunoblotting results showed that levels of LC3-II were significantly higher in brains of mutant than wild-type mice. Combined LC3 immunofluorescence and filipin staining showed that LC3 accumulated within filipin-labeled cholesterol clusters inside Purkinje cells. Electron microscopic examination revealed the existence of autophagic vacuole-like structures and multivesicles in brains from Npc1(-/-) mice. These results provide strong evidence that cholesterol accumulation-induced changes in autophagy-lysosome function are closely associated with neurodegeneration in NPC.
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“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 Liao et al., 2007
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Metadata
- Authors
- Liao, G., Yao, Y., Liu, J., Yu, Z., Cheung, S., Xie, A., Liang, X., & Bi, X.
- Affiliations
- Western University of Health Sciences (US)
- University of California, Irvine (US)
- Academy of Military Medical Sciences (CN)
- Corresponding author
- Bi, Xiaoning
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2007-09
- Volume
- 171
- Issue
- 3
- Pages
- 962-975
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1959498
- OpenAlex
- W2054595666
- Cited by
- 220
- References
- 73
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 14 · 2023: 10 · 2022: 9 · 2021: 12 · 2020: 12 · 2019: 12 · 2018: 10 · 2017: 9 · 2016: 13 · 2015: 10 · 2014: 10 · 2013: 16 · 2012: 10
- FWCI
- 12.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS048423, NS048423)
- Institute of Genetics
- Topics
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Glycogen Storage Diseases and Myoclonus
- Keywords
- Niemann-Pick disease type C, Npc1 knockout mice, intracellular cholesterol accumulation, cathepsin D, neurodegeneration, ubiquitinated proteins, LC3, autophagosomes, Purkinje cells, astrocytes, microglia, postnatal brain development
- MeSH terms
- Niemann-Pick C1 Protein, Animals, Autophagy, Brain, Cathepsin B, Cathepsin D, Child, Cholesterol, Filipin, Humans, Lysosomes, Mice, Inbred BALB C, Microtubule-Associated Proteins, Niemann-Pick Diseases, Proteins, Purkinje Cells, Mice, Knockout, Intracellular Signaling Peptides and Proteins, Mice
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