Browsing by Author "Grazia Spillantini, Maria"
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Item 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 MedicineFilaments 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.Item 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 MedicineCorrection: 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.Item Early-onset Dementia with Lewy Bodies(Wiley, 2004-04) Takao, Masaki; Ghetti, Bernardino; Yoshida, Hirotaka; Piccardo, Pedro; Narain, Yolanda; Murrell, Jill R.; Vidal, Ruben; Glazier, Bradley S.; Jakes, Ross; Tsutsui, Miho; Grazia Spillantini, Maria; Crowther, R. Anthony; Goedert, Michel; Koto, Atsuo; Pathology and Laboratory Medicine, School of MedicineThe clinical and neuropathological characteristics of an atypical form of dementia with Lewy bodies (DLB) are described. The proband experienced difficulties in her school performance at 13 years of age. Neurological examination revealed cognitive dysfunction, dysarthria, parkinsonism and myoclonus. By age 14 years, the symptoms had worsened markedly and the proband died at age 15 years. On neuropathological examination, the brain was severely atrophic. Numerous intracytoplasmic and intraneuritic Lewy bodies, as well as Lewy neurites, were present throughout the cerebral cortex and subcortical nuclel; vacuolar changes were seen in the upper layers of the neocortex and severe neuronal loss and gliosis were evident in the cerebral cortex and substantia nigra. Lewy bodies and Lewy neurites were strongly immunoreactive for alpha-synuclein and ubiquitin. Lewy bodies were composed of filamentous and granular material and isolated filaments were decorated by alpha-synuclein antibodies. Immunohistochemistry for tau or beta-amyloid yielded negative results. The etiology of this atypical form of DLB is unknown, since there was no family history and since sequencing of the exonic regions of alpha-Synuclein, beta-Synuclein, Synphilin-1, Parkin, Ubiquitin C-terminal hydrolase L1 and Neurofilament-M failed to reveal a pathogenic mutation. This study provides further evidence of the clinical and pathological heterogeneity of DLB.Item 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 MedicineThe 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.Item New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy(Springer, 2023) Yang, Yang; Garringer, Holly J.; Shi, Yang; Lövestam, Sofia; Peak‑Chew, Sew; Zhang, Xianjun; Kotecha, Abhay; Bacioglu, Mehtap; Koto, Atsuo; Takao, Masaki; Grazia Spillantini, Maria; Ghetti, Bernardino; Vidal, Ruben; Murzin, Alexey G.; Scheres, Sjors H. W.; Goedert, Michel; Pathology and Laboratory Medicine, School of MedicineA 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36–100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.