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Tuberous sclerosis complex is associated with a novel human tauopathy

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Abstract

Tuberous sclerosis complex (TSC) is a neurogenetic disorder leading to epilepsy, developmental delay, and neurobehavioral dysfunction. The syndrome is caused by pathogenic variants in TSC1 (coding for hamartin) or TSC2 (coding for tuberin). Recently, we reported a progressive frontotemporal dementia-like clinical syndrome in a patient with a mutation in TSC1, but the neuropathological changes seen in adults with TSC with or without dementia have yet to be systematically explored. Here, we examined neuropathological findings in adults with TSC (n = 11) aged 30–58 years and compared them to age-matched patients with epilepsy unrelated to TSC (n = 9) and non-neurological controls (n = 10). In 3 of 11 subjects with TSC, we observed a neurofibrillary tangle-predominant “TSC tauopathy” not seen in epilepsy or non-neurological controls. This tauopathy was observed in the absence of pathological amyloid beta, TDP-43, or alpha-synuclein deposition. The neurofibrillary tangles in TSC tauopathy showed a unique pattern of post-translational modifications, with apparent differences between TSC1 and TSC2 mutation carriers. Tau acetylation (K274, K343) was prominent in both TSC1 and TSC2, whereas tau phosphorylation at a common phospho-epitope (S202) was observed only in TSC2. TSC tauopathy was observed in selected neocortical, limbic, subcortical, and brainstem sites and showed a 3-repeat greater than 4-repeat tau isoform pattern in both TSC1 and TSC2 mutation carriers, but no tangles were immunolabeled with MC1 or p62 antibodies. The findings suggest that individuals with TSC are at risk for a unique tauopathy in mid-life and that tauopathy pathogenesis may involve TSC1, TSC2, and related molecular pathways.

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References

  1. Al-Saleem T, Wessner LL, Scheithauer BW, Patterson K, Roach ES, Dreyer SJ et al (1998) Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 83:2208–2216

    Article  CAS  Google Scholar 

  2. Alquezar C, Schoch KM, Geier EG, Ramos EM, Scrivo A, Li KH et al (2021) TSC1 loss increases risk for tauopathy by inducing tau acetylation and preventing tau clearance via chaperone-mediated autophagy. Sci Adv 7:eabg3897. https://doi.org/10.1126/sciadv.abg3897

    Article  CAS  Google Scholar 

  3. Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969. https://doi.org/10.1097/NEN.0b013e318232a379

    Article  CAS  Google Scholar 

  4. Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I et al (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128:755–766. https://doi.org/10.1007/s00401-014-1349-0

    Article  CAS  Google Scholar 

  5. Curatolo P, Moavero R, de Vries PJ (2015) Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 14:733–745. https://doi.org/10.1016/S1474-4422(15)00069-1

    Article  Google Scholar 

  6. de Vries PJ, Whittemore VH, Leclezio L, Byars AW, Dunn D, Ess KC et al (2015) Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. Pediatr Neurol 52:25–35. https://doi.org/10.1016/j.pediatrneurol.2014.10.004

    Article  Google Scholar 

  7. European Chromosome 16 Tuberous Sclerosis C (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305–1315. https://doi.org/10.1016/0092-8674(93)90618-z

    Article  Google Scholar 

  8. Feliciano DM (2020) The neurodevelopmental pathogenesis of tuberous sclerosis complex (TSC). Front Neuroanat 14:39. https://doi.org/10.3389/fnana.2020.00039

    Article  CAS  Google Scholar 

  9. Grinberg LT, Wang X, Wang C, Sohn PD, Theofilas P, Sidhu M et al (2013) Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol. https://doi.org/10.1007/s00401-013-1080-2

    Article  Google Scholar 

  10. Kerfoot C, Wienecke R, Menchine M, Emelin J, Maize JC Jr, Welsh CT et al (1996) Localization of tuberous sclerosis 2 mRNA and its protein product tuberin in normal human brain and in cerebral lesions of patients with tuberous sclerosis. Brain Pathol 6:367–375. https://doi.org/10.1111/j.1750-3639.1996.tb00866.x

    Article  CAS  Google Scholar 

  11. Liu AJ, Lusk JB, Ervin J, Burke J, O’Brien R, Wang SJ (2022) Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation. Acta Neuropathol Commun 10:27. https://doi.org/10.1186/s40478-022-01330-x

    Article  CAS  Google Scholar 

  12. Liu AJ, Staffaroni AM, Rojas-Martinez JC, Olney NT, Alquezar-Burillo C, Ljubenkov PA et al (2020) Association of cognitive and behavioral features between adults with tuberous sclerosis and frontotemporal dementia. JAMA Neurol 77:358–366. https://doi.org/10.1001/jamaneurol.2019.4284

    Article  Google Scholar 

  13. McKee AC, Cairns NJ, Dickson DW, Folkerth RD, Keene CD, Litvan I et al (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131:75–86. https://doi.org/10.1007/s00401-015-1515-z

    Article  CAS  Google Scholar 

  14. McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH et al (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136:43–64. https://doi.org/10.1093/brain/aws307

    Article  Google Scholar 

  15. Mizuguchi M, Ikeda K, Takashima S (2000) Simultaneous loss of hamartin and tuberin from the cerebrum, kidney and heart with tuberous sclerosis. Acta Neuropathol 99:503–510. https://doi.org/10.1007/s004010051152

    Article  CAS  Google Scholar 

  16. Olney NT, Alquezar C, Ramos EM, Nana AL, Fong JC, Karydas AM et al (2017) Linking tuberous sclerosis complex, excessive mTOR signaling, and age-related neurodegeneration: a new association between TSC1 mutation and frontotemporal dementia. Acta Neuropathol 134:813–816. https://doi.org/10.1007/s00401-017-1764-0

    Article  CAS  Google Scholar 

  17. Palmio J, Suhonen J, Keranen T, Hulkkonen J, Peltola J, Pirttila (2009) Cerebrospinal fluid tau as a marker of neuronal damage after epileptic seizure. Seizure 18:474–477. https://doi.org/10.1016/j.seizure.2009.04.006

    Article  Google Scholar 

  18. Ramlaul K, Fu W, Li H, de Martin GN, He L, Trivedi M et al (2021) Architecture of the tuberous sclerosis protein complex. J Mol Biol 433:166743. https://doi.org/10.1016/j.jmb.2020.166743

    Article  CAS  Google Scholar 

  19. Ramos EM, Dokuru DR, Van Berlo V, Wojta K, Wang Q, Huang AY et al (2019) Genetic screen in a large series of patients with primary progressive aphasia. Alzheimers Dement 15:553–560. https://doi.org/10.1016/j.jalz.2018.10.009

    Article  Google Scholar 

  20. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. https://doi.org/10.1038/gim.2015.30

    Article  Google Scholar 

  21. Salminen A, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H, Alafuzoff I (2012) Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer’s disease. Prog Neurobiol 96:87–95. https://doi.org/10.1016/j.pneurobio.2011.11.005

    Article  CAS  Google Scholar 

  22. Sarnat HB, Flores-Sarnat L (2015) Infantile tauopathies: hemimegalencephaly; tuberous sclerosis complex; focal cortical dysplasia 2; ganglioglioma. Brain Dev 37:553–562. https://doi.org/10.1016/j.braindev.2014.08.010

    Article  Google Scholar 

  23. Togo T, Akiyama H, Iseki E, Uchikado H, Kondo H, Ikeda K et al (2004) Immunohistochemical study of tau accumulation in early stages of Alzheimer-type neurofibrillary lesions. Acta Neuropathol 107:504–508. https://doi.org/10.1007/s00401-004-0842-2

    Article  CAS  Google Scholar 

  24. van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808. https://doi.org/10.1126/science.277.5327.805

    Article  Google Scholar 

  25. Weaver CL, Espinoza M, Kress Y, Davies P (2000) Conformational change as one of the earliest alterations of tau in Alzheimer’s disease. Neurobiol Aging 21:719–727. https://doi.org/10.1016/s0197-4580(00)00157-3

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the NIH NeuroBioBank for providing the human brain tissue. This work was supported by the Rainwater Charitable Foundation, the Bluefield Project to Cure FTD, and NIH Grants P30AG062422, P01AG019724, and U01AG057195.

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Author notes

  1. Aimee W. Kao and William W. Seeley have made equal contributions for this article.

Authors and Affiliations

  1. Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA

    Ji-Hye L. Hwang, Olga S. Perloff, Stephanie E. Gaus, Camila Benitez, Carolina Alquezar, Celica Q. Cosme, Alissa L. Nana, Sarat C. Vatsavayai, Bruce L. Miller, Aimee W. Kao & William W. Seeley

  2. Department of Pathology and Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA

    William W. Seeley

  3. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Eliana M. Ramos

  4. Department of Neurology, Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Daniel H. Geschwind

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  1. Ji-Hye L. Hwang
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Contributions

WWS, AWK conceived and designed the project. JHH performed immunohistochemistry. CB performed western blotting. CA and EMR performed genetic analysis. WWS, OSP, SEG, and JHH wrote the paper. All authors read and critically reviewed the manuscript.

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Correspondence to William W. Seeley.

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Hwang, JH.L., Perloff, O.S., Gaus, S.E. et al. Tuberous sclerosis complex is associated with a novel human tauopathy. Acta Neuropathol 145, 1–12 (2023). https://doi.org/10.1007/s00401-022-02521-5

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  • DOI: https://doi.org/10.1007/s00401-022-02521-5

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