Tau normal function influences Niemann-Pick type C disease pathogenesis in mice and modulates autophagy in NPC1-deficient cells.
Open accessAbstract
The tauopathies are a diverse class of devastating neurodegenerative disorders, characterized by the hyperphosphorylation and aggregation of the microtubule binding protein tau. Niemann-Pick type C disease (NPC) is a tauopathy that affects children,and is caused by mutations in intracellular lipid and cholesterol trafficking proteins. Loss-of-function mutations in the NPC1gene are responsible for 95 percent of all NPC cases, and lead to progressive neurodegeneration and early death. To assess the extent to which tau affects NPC pathology, we generated mice that lack both NPC1 and tau. NPC1/tau double-null mutants exhibit an exacerbated NPC phenotype, including severe systemic manifestations,and die significantly earlier than NPC1 single-null mutants.Since autophagy has been previously implicated in NPC pathogenesis,we investigated the impact of tau deletion on this pathway.Acute reductions of tau in NPC1-deficient fibroblasts significantly decrease autophagic induction and flux, while having no effect on the autophagic pathway in control cells. Here we propose a model in which tau's normal function is critical to the induction of autophagy in NPC1 deficiency, and suggest that this novel mechanism contributes to cellular dysfunction in the tauopathies.
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In seizure disorders such as tuberous sclerosis complex and Niemann-Pick type C disease characterized by autophagy dysregulation, an increase in normal tau levels may in turn contribute to both seizure activity and PTEN inhibition, creating a feedback loop of mTOR overactivation that results in further hyperphosphorylation of tau.
“In seizure disorders such as TSC and NPC that are characterized by autophagy dysregulation (Pacheco et al., 2009; Caccamo et al., 2013), increase in normal tau levels may in turn contribute to both seizure activity and PTEN inhibition, creating a feedback loop of mTOR overactivation that results in further hyperphosphorylation of tau (Figure 3).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Pacheco et al., 2009
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Background
- Authors
- Pacheco, C. D., Elrick, M. J., & Lieberman, A. P.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Lieberman, Andrew P.
- ORCID
- Lieberman, Andrew P.
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2009-05-16
- Volume
- 5
- Issue
- 4
- Pages
- 548-550
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC2704906
- OpenAlex
- W2094646374
- Cited by
- 20
- References
- 27
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2014: 2 · 2013: 1 · 2012: 3
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (F31NS051143)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- tau protein, Niemann-Pick disease type C, NPC1, tauopathy, autophagic flux, neurodegeneration, cholesterol transport, lipid trafficking, tau hyperphosphorylation
- MeSH terms
- Niemann-Pick C1 Protein, Animals, Autophagy, Fibroblasts, Models, Biological, Phenotype, Proteins, tau Proteins, Gene Deletion, Intracellular Signaling Peptides and Proteins, Mice, Niemann-Pick Disease, Type C, Gene Knockdown Techniques
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