Cited by 221Lysosomal Storage Disorders ResearchAutophagy in Disease and TherapyGlycogen Storage Diseases and Myoclonus

Cholesterol Accumulation Is Associated with Lysosomal Dysfunction and Autophagic Stress in Npc1−/− Mouse Brain

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Liao, Guanghong, Yao, Yueqin, Liu, Jihua, Yu, Zhang, Cheung, Simon, Xie, Ang, Liang, Xiaoli, Bi, Xiaoning·2007·The American Journal of Pathology

Abstract

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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Crossref · 10.2353/ajpath.2007.070052

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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 Liao et al., 2007

    The sections on increased cathepsin D levels and early-onset lysosomal abnormality report higher cathepsin D levels and activity in Npc1−/− mouse brains (page not provided). They do not show that NPC1 interacts directly with CTSD or affects its stability or turnover. Progranulin is supported by a separate citation, not the one audited here. (LLM, conf=0.88)

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Research works printed but not linked: 3

  1. Auer IA, Schmidt ML, Lee VM, Curry B, Suzuki K, Shin RW, Pentchev PG, Carstea ED, Trojanowski JQ: Paired helical filament tau (PHFtau) Autophagic Dysfunction in Npc1 Ϫ/Ϫ Mice 973 AJP September 2007, Vol. 171, No. 3
  2. in Niemann-Pick type C disease is similar to PHFtau in Alzheimer's disease. Acta Neuropathol (Berl) 1995, 90:547-551
  3. Bi X, Liu J, Yao Y, Baudry M, Lynch G: Deregulation of GSK-3␤ and NF-B is associated with neurodegeneration in Npc1 Ϫ/Ϫ mouse brain. Am J Pathol 2005, 167:1081-1092

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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)
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
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 › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Rheumatology › 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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