Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration
Open accessAbstract
Tuberous sclerosis complex (TSC) is a neurogenetic disorder that often causes brain abnormalities leading to epilepsy, developmental delay, and autism. TSC is caused by inactivating mutations in either of the genes encoding the proteins hamartin (TSC1) and tuberin (TSC2). These proteins form a heterodimer that inhibits the mammalian target of rapamycin complex 1 (mTORC1) pathway, controlling translation and cell growth. Loss of either protein results in dysregulated mTORC1 activation, an important aspect of TSC pathogenesis. About thirty percent of TSC patients have cerebellar pathology that is poorly understood. To investigate the effects of TSC on the cerebellum, we created a mouse model in which the Tsc2 gene was selectively deleted from Purkinje cells starting at postnatal day 6 (P6). The loss of Tsc2 caused a progressive increase in Purkinje cell size and subsequent death from apoptosis. Purkinje cell loss was predominantly cell type specific and associated with motor deficits. Immunohistochemical analysis showed that both endoplasmic reticulum (ER) and oxidative stress were increased in Tsc2-null Purkinje cells. The cell death and ER stress phenotypes were rescued by treatment with the mTORC1 inhibitor rapamycin. To assess whether the murine Purkinje cell loss has a correlate to the human TSC, we analyzed postmortem cerebellum samples from TSC patients and detected Purkinje cell loss in half of the samples. Our results establish a critical role for the TSC complex in Purkinje cell survival by regulating ER and oxidative stress and reveal a novel aspect of TSC neuropathology.
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During periods of oxidative stress, loss of TSC2 results in Purkinje cell degeneration.
“During periods of oxidative stress, loss of the TSC2 results in purkinje cell degeneration [44].”
From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [44]
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- Authors
- Reith, R. M., Way, S., McKenna, J., Haines, K., & Gambello, M. J.
- Affiliations
- The University of Texas Health Science Center at Houston (US)
- Corresponding author
- Gambello, Michael J.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 43
- Issue
- 1
- Pages
- 113-122
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC3096682
- OpenAlex
- W2005374119
- Cited by
- 65
- References
- 62
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 4 · 2015: 8 · 2014: 11 · 2013: 6 · 2012: 9
- FWCI
- 6.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIH/NINDS (RO1NS060804)
- DOD (W81XWH-07-1-0275)
- NIH/NCRR (TL1RR024147)
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- tuberous sclerosis complex, tuberin, TSC2, hamartin, Purkinje cells, Purkinje cell degeneration, mTORC1, endoplasmic reticulum stress, oxidative stress, apoptosis, cerebellum, motor impairment, rapamycin, mouse model
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Adult, Animals, Cell Survival, Disease Models, Animal, Endoplasmic Reticulum, Female, Humans, Mice, Inbred C57BL, Mice, Mutant Strains, Middle Aged, Purkinje Cells, Tuberous Sclerosis, Apoptosis, Oxidative Stress, Tumor Suppressor Proteins, Cell Size, Mice, Mice, 129 Strain
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