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Cited by 102Lysosomal Storage Disorders ResearchNeuroinflammation and Neurodegeneration MechanismsMetabolism and Genetic Disorders

The Role of Attenuated Astrocyte Activation in Infantile Neuronal Ceroid Lipofuscinosis

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Macauley, Shannon L., Pekny, Milos, Sands, Mark S.·2011·The Journal of Neuroscience
DOI 10.1523/jneurosci.3579-11.2011PMC PMC3218425
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Abstract

Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited neurodegenerative disorder affecting the CNS during infancy. INCL is caused by mutations in the CLN1 gene that lead to a deficiency in the lysosomal hydrolase, palmitoyl protein thioesterase 1 (PPT1). A murine model of INCL, the PPT1-deficient (PPT1(-/-)) mouse, is an accurate phenocopy of the human disease. The first pathological change observed in the PPT1(-/-) brain is regional areas of glial fibrillary acidic protein (GFAP) upregulation, which predicts future areas of neurodegeneration. We hypothesized that preventing GFAP and vimentin upregulation in reactive astrocytes will alter the CNS disease. To test this hypothesis, we generated mice simultaneously carrying null mutations in the GFAP, Vimentin, and PPT1 genes (GFAP(-/-)Vimentin(-/-)PPT1(-/-)). Although the clinical and pathological features of the GFAP(-/-)Vimentin(-/-)PPT1(-/-) mice are similar to INCL, the disease appears earlier and progresses more rapidly. One mechanism underlying this accelerated phenotype is a profound neuroinflammatory response within the CNS. Thus, our data identify a protective role for intermediate filament upregulation during astrocyte activation in INCL, a model of chronic neurodegeneration.

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  • Attenuated reactive gliosis in Gfap−/−Vim−/− mice was connected with larger infarctions in focal brain ischemia and facilitated disease progression in Batten's disease.

    “Attenuated reactive gliosis in Gfap−/− Vim−/− mice was connected with larger infarctions in a mouse model of focal brain ischemia (32) and facilitated disease progression in a mouse model of Batten's disease (33).”

    From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [33]

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Authors
Macauley, S. L., Pekny, M., & Sands, M. S.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Sands, Mark S.
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2011-10-26
Volume
31
Issue
43
Pages
15575-15585
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.3579-11.2011
PMC
PMC3218425
OpenAlex
W2102542024
Cited by
102
References
48
Citations by year
2026: 5 · 2025: 4 · 2024: 2 · 2022: 6 · 2021: 4 · 2020: 5 · 2019: 8 · 2018: 6 · 2017: 9 · 2016: 7 · 2015: 11 · 2014: 15 · 2013: 12 · 2012: 8
FWCI
7.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Funders
  • Batten Disease Support and Research Association
  • National Institutes of Health
  • Medical Research Council
  • National Institute of Neurological Disorders and Stroke (NS043105, NS056728, R01NS043205, R44NS043105)
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
infantile neuronal ceroid lipofuscinosis, CLN1, PPT1, reactive astrocytes, astrocyte activation, glial fibrillary acidic protein, vimentin, intermediate filaments, neuroinflammation, neurodegeneration, triple knockout mice, lysosomal storage disease
MeSH terms
Analysis of Variance, Animals, Astrocytes, Blood-Testis Barrier, Brain, Capillary Permeability, Cerebral Cortex, Disease Models, Animal, Glial Fibrillary Acidic Protein, Humans, Intermediate Filaments, Longevity, Mice, Inbred C57BL, Neuronal Ceroid-Lipofuscinoses, Organ Size, RNA, Messenger, Thiolester Hydrolases, Vimentin, Up-Regulation, Cytokines, Silver Staining, Mice, Knockout, Disease Progression, Infarction, Middle Cerebral Artery, Mice

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