Microtubule Cytoskeletal Network Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders
Open accessAbstract
Tuberous sclerosis complex (TSC) is a rare genetic multisystem disorder caused by loss-of-function mutations in the tumour suppressors TSC1/TSC2, both of which are negative regulators of the mammalian target of rapamycin (mTOR) kinase. Importantly, mTOR hyperactivity seems to be linked with the pathobiology of autism spectrum disorders (ASD). Recent studies suggest the potential involvement of microtubule (MT) network dysfunction in the neuropathology of “mTORopathies”, including ASD. Cytoskeletal reorganization could be responsible for neuroplasticity disturbances in ASD individuals. Thus, the aim of this work was to study the effect of Tsc2 haploinsufficiency on the cytoskeletal pathology and disturbances in the proteostasis of the key cytoskeletal proteins in the brain of a TSC mouse model of ASD. Western-blot analysis indicated significant brain-structure-dependent abnormalities in the microtubule-associated protein Tau (MAP-Tau), and reduced MAP1B and neurofilament light (NF-L) protein level in 2-month-old male B6;129S4-Tsc2tm1Djk/J mice. Alongside, pathological irregularities in the ultrastructure of both MT and neurofilament (NFL) networks as well as swelling of the nerve endings were demonstrated. These changes in the level of key cytoskeletal proteins in the brain of the autistic-like TSC mice suggest the possible molecular mechanisms responsible for neuroplasticity alterations in the ASD brain.
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Neurons with heightened mTOR activity, particularly hippocampal CA1 neurons, are selectively predisposed to tau accumulation and degeneration.
“Experimental data further indicate that neurons with heightened mTOR activityparticularly hippocampal CA1 neurons, a region highly vulnerable in AD-are selectively predisposed to tau accumulation and degeneration, implicating mTOR dysregulation as a central upstream driver (14,15).”
From Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention (2026) · cites this paper as [15]
The Discussion reports increased tau levels and phosphorylation in the hippocampus of mice with elevated mTOR signalling, supporting an mTOR–tau link. It does not identify CA1 neurons as selectively predisposed or show that those neurons degenerate; the reported findings concern brain regions and cytoskeletal changes, not selective neuronal degeneration. (LLM, conf=0.87)
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- Authors
- Gąssowska-Dobrowolska, M., Czapski, G. A., Cieślik, M., Zajdel, K., Frontczak-Baniewicz, M., Babiec, L., & Adamczyk, A.
- Affiliations
- Mossakowski Medical Research Institute, Polish Academy of Sciences (PL)
- Electron Microscopy Research Unit, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland
- Corresponding author
- Gąssowska-Dobrowolska, Magdalena
- ORCID
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2023-04-15
- Volume
- 24
- Issue
- 8
- Pages
- 7303
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC10138344
- OpenAlex
- W4366091010
- Cited by
- 10
- References
- 134
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 1 · 2023: 2
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Science Centre (2017/25/B/NZ4/01969)
- Mossakowski Medical Research Institute, Polish Academy of Sciences (2017/25/B/NZ4/01969)
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- tuberous sclerosis complex, autism spectrum disorder, microtubule cytoskeleton, mTORopathies, tau protein, MAP1B, neurofilament light chain, neuroplasticity, B6
- MeSH terms
- Autism Spectrum Disorder, Animals, Cytoskeletal Proteins, Male, Mammals, Microtubules, Tuberous Sclerosis, Mice, TOR Serine-Threonine Kinases
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