Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging
| العنوان: | Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging |
|---|---|
| المؤلفون: | Jolien Perneel, Manuela Neumann, Bavo Heeman, Simon Cheung, Marleen Van den Broeck, Sarah Wynants, Matt Baker, Cristina T. Vicente, Júlia Faura, Rosa Rademakers, Ian R. A. Mackenzie |
| المصدر: | Acta neuropathologica Acta neuropathologica 145, 285–302 (2023). doi:10.1007/s00401-022-02531-3 |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | metabolism [Nerve Tissue Proteins], Neurodegenerative disease, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, genetics [Membrane Proteins], FTLD-TDP, TMEM106B, genetics [Neurodegenerative Diseases], genetics [Aging], pathology [Frontotemporal Dementia], Humans, Intercellular Signaling Peptides and Proteins, Neurology (clinical), ddc:610, genetics [Frontotemporal Lobar Degeneration], Human medicine, genetics [Frontotemporal Dementia], metabolism [Membrane Proteins], genetics [Nerve Tissue Proteins], Frontotemporal dementia, GRN |
| الوصف: | Several studies using cryogenic electron microscopy (cryo-EM) techniques recently reported the isolation and characterization of novel protein filaments, composed of a C-terminal fragment (CTF) of the endolysosomal transmembrane protein 106B (TMEM106B), from human post-mortem brain tissue with various neurodegenerative conditions and normal aging. Genetic variation in TMEM106B is known to influence the risk and presentation of several neurodegenerative diseases, especially frontotemporal dementia (FTD) caused by mutations in the progranulin gene (GRN). To further elucidate the significance of TMEM106B CTF, we performed immunohistochemistry with antibodies directed against epitopes within the filament-forming C-terminal region of TMEM106B. Accumulation of TMEM106B C-terminal immunoreactive (TMEM-ir) material was a common finding in all the conditions evaluated, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), Alzheimer's disease, tauopathies, synucleinopathies and neurologically normal aging. TMEM-ir material was present in a wide range of brain cell types and in a broad neuroanatomical distribution; however, there was no co-localization of TMEM-ir material with other neurodegenerative proteins in cellular inclusions. In most conditions, the presence and abundance of TMEM-ir aggregates correlated strongly with patient age and showed only a weak correlation with the TMEM106B haplotype or the primary pathological diagnosis. However, all patients with FTD caused by GRN mutations were found to have high levels of TMEM-ir material, including several who were relatively young (< 60 years). These findings suggest that the accumulation of TMEM106B CTF is a common age-related phenomenon, which may reflect lysosomal dysfunction. Although its significance in most neurodegenerative conditions remains uncertain, the consistent finding of extensive TMEM-ir material in cases of FTLD-TDP with GRN mutations further supports a pathomechanistic role of TMEM106B and lysosomal dysfunction in this specific disease population. |
| تدمد: | 1432-0533 0001-6322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f653debe7e6fec04abdff5fe904a6339Test https://pubmed.ncbi.nlm.nih.gov/36607424Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....f653debe7e6fec04abdff5fe904a6339 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14320533 00016322 |
|---|