Browsing by Author "Katsinelos, Taxiarchis"

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    Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems
    (Springer Nature, 2024-06-17) Bacioglu, Mehtap; Schweighauser, Manuel; Gray, Derrick; Lövestam, Sofia; Katsinelos, Taxiarchis; Quaegebeur, Annelies; van Swieten, John; Jaunmuktane, Zane; Davies, Stephen W.; Scheres, Sjors H. W.; Goedert, Michel; Ghetti, Bernardino; Grazia Spillantini, Maria; Biochemistry and Molecular Biology, School of Medicine
    Filaments made of residues 120-254 of transmembrane protein 106B (TMEM106B) form in an age-dependent manner and can be extracted from the brains of neurologically normal individuals and those of subjects with a variety of neurodegenerative diseases. TMEM106B filament formation requires cleavage at residue 120 of the 274 amino acid protein; at present, it is not known if residues 255-274 form the fuzzy coat of TMEM106B filaments. Here we show that a second cleavage appears likely, based on staining with an antibody raised against residues 263-274 of TMEM106B. We also show that besides the brain TMEM106B inclusions form in dorsal root ganglia and spinal cord, where they were mostly found in non-neuronal cells. We confirm that in the brain, inclusions were most abundant in astrocytes. No inclusions were detected in heart, liver, spleen or hilar lymph nodes. Based on their staining with luminescent conjugated oligothiophenes, we confirm that TMEM106B inclusions are amyloids. By in situ immunoelectron microscopy, TMEM106B assemblies were often found in structures resembling endosomes and lysosomes.
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    Correction: Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems
    (Springer Nature, 2024-08-14) Bacioglu, Mehtap; Gray, Derrick; Lövestam, Sofia; Katsinelos, Taxiarchis; Quaegebeur, Annelies; van Swieten, John; Jaunmuktane, Zane; Davies, Stephen W.; Scheres, Sjors H. W.; Goedert, Michel; Ghetti, Bernardino; Grazia Spillantini, Maria; Pathology and Laboratory Medicine, School of Medicine
    Correction: Acta Neuropathologica Communications (2024) 12:99 10.1186/s40478-024-01813-z Following publication of the original article [1], the sentence “It remains to be determined if the formation of TMEM106B filaments can influence the risk of developing neurodegenerative diseases” in the paragraph starting with “Abundant filaments made of residues” under Discussion heading gives the relevant meaning of the previous sentence. The author wants to delete the sentence. The original article has been corrected.
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    Microglia become hypofunctional and release metalloproteases and tau seeds when phagocytosing live neurons with P301S tau aggregates
    (American Association for the Advancement of Science, 2021) Brelstaff, Jack H.; Mason, Matthew; Katsinelos, Taxiarchis; McEwan, William A.; Ghetti, Bernardino; Tolkovsky, Aviva M.; Grazia Spillantini, Maria; Pathology and Laboratory Medicine, School of Medicine
    The microtubule-associated protein tau aggregates in multiple neurodegenerative diseases, causing inflammation and changing the inflammatory signature of microglia by unknown mechanisms. We have shown that microglia phagocytose live neurons containing tau aggregates cultured from P301S tau mice due to neuronal tau aggregate-induced exposure of the “eat me” signal phosphatidylserine. Here, we show that after phagocytosing tau aggregate-bearing neurons, microglia become hypophagocytic while releasing seed-competent insoluble tau aggregates. These microglia express a senescence-like phenotype, demonstrated by acidic β-galactosidase activity, secretion of paracrine senescence-associated cytokines, and maturation of matrix remodeling enzymes, results that are corroborated in P301S mouse brains and ex vivo brain slices. In particular, the nuclear factor κB–dependent activation of matrix metalloprotease 3 (MMP3/stromelysin1) was replicated in brains from patients with tauopathy. These data show that microglia that have been activated to ingest live tau aggregates-bearing neurons behave hormetically, becoming hypofunctional while acting as vectors of tau aggregate spreading.
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    TMEM106B amyloid filaments in the Biondi bodies of ependymal cells
    (Springer, 2024-11-06) Ghetti, Bernardino; Schweighauser, Manuel; Jacobsen, Max H.; Gray, Derrick; Bacioglu, Mehtap; Murzin, Alexey G.; Glazier, Bradley S.; Katsinelos, Taxiarchis; Vidal, Ruben; Newell, Kathy L.; Gao, Sujuan; Garringer, Holly J.; Spillantini, Maria Grazia; Scheres, Sjors H. W.; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
    Biondi bodies are filamentous amyloid inclusions of unknown composition in ependymal cells of the choroid plexuses, ependymal cells lining cerebral ventricles and ependymal cells of the central canal of the spinal cord. Their formation is age-dependent and they are commonly associated with a variety of neurodegenerative conditions, including Alzheimer's disease and Lewy body disorders. Here, we show that Biondi bodies are strongly immunoreactive with TMEM239, an antibody specific for inclusions of transmembrane protein 106B (TMEM106B). Biondi bodies were labelled by both this antibody and the amyloid dye pFTAA. Many Biondi bodies were also labelled for TMEM106B and the lysosomal markers Hexosaminidase A and Cathepsin D. By transmission immuno-electron microscopy, Biondi bodies of choroid plexuses were decorated by TMEM239 and were associated with structures that resembled residual bodies or secondary lysosomes. By electron cryo-microscopy, TMEM106B filaments from Biondi bodies of choroid plexuses were similar (Biondi variant), but not identical, to the fold I that was previously identified in filaments from brain parenchyma.