IU Indianapolis ScholarWorks :: Browsing by Author "Murzin, Alexey G."

Browsing by Author "Murzin, Alexey G."

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Age-dependent formation of TMEM106B amyloid filaments in human brains
(Springer Nature, 2022) Schweighauser, Manuel; Arseni, Diana; Bacioglu, Mehtap; Huang, Melissa; Lövestam, Sofia; Shi, Yang; Yang, Yang; Zhang, Wenjuan; Kotecha, Abhay; Garringer, Holly J.; Vidal, Ruben; Hallinan, Grace I.; Newell, Kathy L.; Tarutani, Airi; Murayama, Shigeo; Miyazaki, Masayuki; Saito, Yuko; Yoshida, Mari; Hasegawa, Kazuko; Lashley, Tammaryn; Revesz, Tamas; Kovacs, Gabor G.; van Swieten, John; Takao, Masaki; Hasegawa, Masato; Ghetti, Bernardino; Spillantini, Maria Grazia; Ryskeldi-Falcon, Benjamin; Murzin, Alexey G.; Goedert, Michel; Scheres, Sjors H.W.; Pathology and Laboratory Medicine, School of Medicine
Many age-dependent neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β, α-synuclein and transactive response DNA-binding protein (TARDBP; also known as TDP-43) are the most common1,2. Here we used structure determination by cryogenic electron microscopy to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains. We determined the structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including those resulting from sporadic and inherited tauopathies, amyloid-β amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 individuals with normal neurology and no or only a few amyloid deposits. We observed three TMEM106B folds, with no clear relationships between folds and diseases. TMEM106B filaments correlated with the presence of a 29-kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions, as detected by an antibody specific to the carboxy-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, individuals with normal neurology indicates that they form in an age-dependent manner.
Correction to: Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607
(SpringerLink, 2021-06) 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
Correction to: Acta Neuropathologica 10.1007/s00401-021-02294-3
Cryo-EM structures of amyloid-β 42 filaments from human brains
(American Association for the Advancement of Science, 2022) Yang, Yang; Arseni, Diana; Zhang, Wenjuan; Huang, Melissa; Lövestam, Sofia; Schweighauser, Manuel; Kotecha, Abhay; Murzin, Alexey G.; Peak-Chew, Sew Y.; Macdonald, Jennifer; Lavenir, Isabelle; Garringer, Holly J.; Gelpi, Ellen; Newell, Kathy L.; Kovacs, Gabor G.; Vidal, Ruben; Ghetti, Bernardino; Falcon, Benjamin; Scheres, Sjors H.W.; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
Filament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer’s disease. Here, we report the cryo–electron microscopy (cryo-EM) structures of Aβ42 filaments from human brains. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer’s disease, and type II filaments were found in individuals with familial Alzheimer’s disease and other conditions. The structures of Aβ42 filaments from the brain differ from those of filaments assembled in vitro. By contrast, in AppNL-F knock-in mice, Aβ42 deposits were made of type II filaments. Knowledge of Aβ42 filament structures from human brains may lead to the development of inhibitors of assembly and improved imaging agents.
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 tau filaments from Alzheimer's disease
(Springer Nature, 2017-07-13) Fitzpatrick, Anthony W.P.; Falcon, Benjamin; He, Shaoda; Murzin, Alexey G.; Murshudov, Garib; Garringer, Holly J.; Crowther, R. Anthony; Ghetti, Bernardino; Goedert, Michel; Scheres, Sjors H.W.; Pathology and Laboratory Medicine, School of Medicine
Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.
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.
Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C
(Springer Nature, 2024) Arseni, Diana; Nonaka, Takashi; Jacobsen, Max H.; Murzin, Alexey G.; Cracco, Laura; Peak-Chew, Sew Y.; Garringer, Holly J.; Kawakami, Ito; Suzuki, Hisaomi; Onaya, Misumoto; Saito, Yuko; Murayama, Shigeo; Geula, Changiz; Vidal, Ruben; Newell, Kathy L.; Mesulam, Marsel; Ghetti, Bernardino; Hasegawa, Masato; Ryskeldi-Falcon, Benjamin; Pathology and Laboratory Medicine, School of Medicine
Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system1. Human genetic studies have established a causal role for protein assembly in neurodegeneration2. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in cryo-electron microscopy have enabled the structures of the protein filaments to be determined from the brains of patients1. All neurodegenerative diseases studied to date have been characterized by the self-assembly of proteins in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) types A and B3,4. Here we used cryo-electron microscopy to determine filament structures from the brains of individuals with FTLD-TDP type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains. Regions of TDP-43 and ANXA11 that were previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as an approximately 22 kDa N-terminal fragment lacking the annexin core domain. Immunohistochemistry of brain sections showed the colocalization of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP type C. This work establishes a central role for ANXA11 in FTLD-TDP type C. The unprecedented formation of heteromeric amyloid filaments in the human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.
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 chronic traumatic encephalopathy encloses hydrophobic molecules
(Springer Nature, 2019-04) Falcon, Benjamin; Zivanov, Jasenko; Zhang, Wenjuan; Murzin, Alexey G.; Garringer, Holly J.; Vidal, Ruben; Crowther, R. Anthony; Newell, Kathy L.; Ghetti, Bernardino; Goedert, Michel; Scheres, Sjors H.W.; Pathology & Laboratory Medicine, IU School of Medicine
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers1-3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4-7. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies10,11. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro12-15. Similar to Alzheimer's disease12,14,16-18, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.

Browsing by Author "Murzin, Alexey G."

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