IU Indianapolis ScholarWorks :: Browsing by Author "Scheres, Sjors H. W."

Browsing by Author "Scheres, Sjors H. W."

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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.
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.
Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains
(Springer, 2023) Yang, Yang; Zhang, Wenjuan; Murzin, Alexey G.; Schweighauser, Manuel; Huang, Melissa; Lövestam, Sofia; Peak‑Chew, Sew Y.; Saito, Takashi; Saido, Takaomi C.; Macdonald, Jennifer; Lavenir, Isabelle; Ghetti, Bernardino; Graff, Caroline; Kumar, Amit; Nordberg, Agneta; Goedert, Michel; Scheres, Sjors H. W.; Pathology and Laboratory Medicine, School of Medicine
The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-β (Aβ)], causes dominantly inherited Alzheimer’s disease. Here, we report the high-resolution cryo-EM structures of Aβ filaments from the frontal cortex of a previously described case (AβPParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12–V40 (human Arctic fold A) and E11–G37 (human Arctic fold B). They have a substructure (residues F20–G37) in common with the folds of type I and type II Aβ42. When compared to the structures of wild-type Aβ42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant Aβ molecules and promote filament formation. A minority of Aβ42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of Aβ filaments with the Arctic mutation from mouse knock-in line AppNL−G−F. Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 (AppNL−G−F murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The AppNL−G−F murine Arctic fold differs from the human Arctic folds, but shares some substructure.
Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer’s disease and cerebral amyloid angiopathy
(Springer Nature, 2023-12-04) Yang, Yang; Murzin, Alexey G.; Peak-Chew, Sew; Franco, Catarina; Garringer, Holly J.; Newell, Kathy L.; Ghetti, Bernardino; Goedert, Michel; Scheres, Sjors H. W.; Pathology and Laboratory Medicine, School of Medicine
We used electron cryo-microscopy (cryo-EM) to determine the structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. In agreement with previously reported structures, which were solved to a resolution of 4.4 Å, we found three types of filaments. However, our new structures, solved to a resolution of 2.4 Å, revealed differences in the sequence assignment that redefine the fold of Aβ40 peptides and their interactions. Filaments are made of pairs of protofilaments, the ordered core of which comprises D1-G38. The different filament types comprise one, two or three protofilament pairs. In each pair, residues H14-G37 of both protofilaments adopt an extended conformation and pack against each other in an anti-parallel fashion, held together by hydrophobic interactions and hydrogen bonds between main chains and side chains. Residues D1-H13 fold back on the adjacent parts of their own chains through both polar and non-polar interactions. There are also several additional densities of unknown identity. Sarkosyl extraction and aqueous extraction gave the same structures. By cryo-EM, parenchymal deposits of Aβ42 and blood vessel deposits of Aβ40 have distinct structures, supporting the view that Alzheimer's disease and cerebral amyloid angiopathy are different Aβ proteinopathies.
Cryo-EM Structures of Chronic Traumatic Encephalopathy Tau Filaments with PET Ligand Flortaucipir
(Elsevier, 2023) Shi, Yang; Ghetti, Bernardino; Goedert, Michel; Scheres, Sjors H. W.; Pathology and Laboratory Medicine, School of Medicine
Positron emission tomography (PET) imaging allows monitoring the progression of amyloid aggregation in the living brain. [18F]-Flortaucipir is the only approved PET tracer compound for the visualisation of tau aggregation. Here, we describe cryo-EM experiments on tau filaments in the presence and absence of flortaucipir. We used tau filaments isolated from the brain of an individual with Alzheimer's disease (AD), and from the brain of an individual with primary age-related tauopathy (PART) with a co-pathology of chronic traumatic encephalopathy (CTE). Unexpectedly, we were unable to visualise additional cryo-EM density for flortaucipir for AD paired helical or straight filaments (PHFs or SFs), but we did observe density for flortaucipir binding to CTE Type I filaments from the case with PART. In the latter, flortaucipir binds in a 1:1 molecular stoichiometry with tau, adjacent to lysine 353 and aspartate 358. By adopting a tilted geometry with respect to the helical axis, the 4.7 Å distance between neighbouring tau monomers is reconciled with the 3.5 Å distance consistent with π-π-stacking between neighbouring molecules of flortaucipir.
Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607
(Springer, 2021-05) Shi, Yang; Murzin, Alexey G.; Falcon, Benjamin; Epstein, Alexander; Machin, Jonathan; Tempest, Paul; Newell, Kathy L.; Vidal, Ruben; Garringer, Holly J.; Sahara, Naruhiko; Higuchi, Makoto; Ghetti, Bernardino; Jang, Ming‑Kuei; Scheres, Sjors H. W.; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
Tau and Aβ assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.
Mutation ∆K281 in MAPT causes Pick’s disease
(Springer, 2023) Schweighauser, Manuel; Garringer, Holly J.; Klingstedt, Therése; Nilsson, K. Peter R.; Masuda‑Suzukake, Masami; Murrell, Jill R.; Risacher, Shannon L.; Vidal, Ruben; Scheres, Sjors H. W.; Goedert, Michel; Ghetti, Bernardino; Newell, Kathy L.; Pathology and Laboratory Medicine, School of Medicine
Two siblings with deletion mutation ∆K281 in MAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in neurons and glial cells of neocortex and some subcortical regions, including hippocampus, caudate/putamen and globus pallidus. The inclusions were argyrophilic with Bodian silver, but not with Gallyas-Braak silver. They were not labelled by an antibody specific for tau phosphorylated at S262 and/or S356. The inclusions were stained by luminescent conjugated oligothiophene HS-84, but not by bTVBT4. Electron cryo-microscopy revealed that the core of tau filaments was made of residues K254-F378 of 3R Tau and was indistinguishable from that of Pick's disease. We conclude that MAPT mutation ∆K281 causes Pick's disease.
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 Medicine
A 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.
Novel tau filament fold in corticobasal degeneration
(Nature Publishing group, 2020-02-12) Zhang, Wenjuan; Tarutani, Airi; Newell, Kathy L.; Murzin, Alexey G.; Matsubara, Tomoyasu; Falcon, Benjamin; Vidal, Ruben; Garringer, Holly J.; Shi, Yang; Ikeuchi, Takeshi; Murayama, Shigeo; Ghetti, Bernardino; Hasegawa, Masato; Goedert, Michel; Scheres, Sjors H. W.; Pathology and Laboratory Medicine, School of Medicine
Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterised by motor and cognitive disturbances (1–3). A higher frequency of the H1 haplotype of MAPT, the tau gene, is present in cases of CBD than in controls (4,5) and genome-wide association studies have identified additional risk factors (6). By histology, astrocytic plaques are diagnostic of CBD (7,8), as are detergent-insoluble tau fragments of 37 kDa by SDS-PAGE (9). Like progressive supranuclear palsy (PSP), globular glial tauopathy (GGT) and argyrophilic grain disease (AGD) (10), CBD is characterised by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R) (11–15). This distinguishes 4R tauopathies from Pick’s disease, filaments of which are made of three-repeat (3R) tau isoforms, and from Alzheimer’s disease and chronic traumatic encephalopathy (CTE), where both 3R and 4R tau isoforms are found in the filaments (16). Here we report the structures of tau filaments extracted from the brains of three individuals with CBD using electron cryo-microscopy (cryo-EM). They were identical between cases, but distinct from those of Alzheimer’s disease, Pick’s disease and CTE (17–19). The core of CBD filaments comprises residues K274-E380 of tau, spanning the last residue of R1, the whole of R2, R3 and R4, as well as 12 amino acids after R4. It adopts a novel four-layered fold, which encloses a large non-proteinaceous density. The latter is surrounded by the side chains of lysine residues 290 and 294 from R2 and 370 from the sequence after R4. CBD is the first 4R tauopathy with filaments of known structure.
Novel tau filament folds in individuals with MAPT mutations P301L and P301T
(bioRxiv, 2024-08-17) Schweighauser, Manuel; Shi, Yang; Murzin, Alexey G.; Garringer, Holly J.; Vidal, Ruben; Murrell, Jill R.; Erro, M. Elena; Seelaar, Harro; Ferrer, Isidro; van Swieten, John C.; Ghetti, Bernardino; Scheres, Sjors H. W.; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
Mutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with abundant filamentous tau inclusions in brain cells. Individuals with pathological MAPT variants exhibit behavioural changes, cognitive impairment and signs of parkinsonism. Missense mutations of residue P301, which are the most common MAPT mutations associated with FTDP-17, give rise to the assembly of mutant four-repeat tau into filamentous inclusions, in the absence of extracellular deposits. Here we report the cryo-EM structures of tau filaments from five individuals belonging to three unrelated families with mutation P301L and from one individual belonging to a family with mutation P301T. A novel three-lobed tau fold resembling the two-layered tau fold of Pick's disease was present in all cases with the P301L tau mutation. Two different tau folds were found in the case with mutation P301T, the less abundant of which was a variant of the three-lobed fold. The major P301T tau fold was V-shaped, with partial similarity to the four-layered tau folds of corticobasal degeneration and argyrophilic grain disease. These findings suggest that FTDP-17 with mutations in P301 should be considered distinct inherited tauopathies and that model systems with these mutations should be used with caution in the study of sporadic tauopathies.

Browsing by Author "Scheres, Sjors H. W."

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