Tuberous Sclerosis Complex is associated with a novel human tauopathy
| Autor: | Ji-Hye L. Hwang, Olga S. Perloff, Stephanie E. Gaus, Camila Benitez, Carolina Alquezar, Celica Q. Cosme, Alissa L. Nana, Sarat C. Vatsavayai, Eliana M. Ramos, Daniel H. Geschwind, Bruce L. Miller, Aimee W. Kao, William W. Seeley |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Adult
Aging Intellectual and Developmental Disabilities (IDD) Clinical Sciences Neurodegenerative Alzheimer's Disease Article Pathology and Forensic Medicine Neurofibrillary tangle Cellular and Molecular Neuroscience Rare Diseases Tuberous Sclerosis Clinical Research Acquired Cognitive Impairment Humans 2.1 Biological and endogenous factors Aetiology Alzheimer's Disease Related Dementias (ADRD) Epilepsy Amyloid beta-Peptides Neurology & Neurosurgery Tumor Suppressor Proteins Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Acetylation TSC2 TSC1 Brain Disorders Tauopathy Frontotemporal Dementia (FTD) Tauopathies Tuberous sclerosis complex Mutation Neurological Dementia Neurology (clinical) Tau |
| Zdroj: | Acta Neuropathol Acta neuropathologica, vol 145, iss 1 |
| Popis: | 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 30-58years 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. |
| Databáze: | OpenAIRE |
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