Biology subjects

Tarutani, A.

Publications and source records attributed to Tarutani, A..

9 recordsLinked to original sources

bioRxiv2026

Oligodendrocytes may provide the extra density of α-synuclein filaments from multiple system atrophy

Prion-like templated seeding of a-synuclein filaments is thought to underlie the spreading of multiple system atrophy (MSA) and other synucleinopathies through the brain. Here, we used -synuclein filaments extracted from the brains of individuals with MSA to induce seeded aggregation in undifferentiated human neuroblastoma SH-SY5Y cells, human iNeurons, mixed primary murine cortical cells and murine oligodendrocyte-enriched primary cultures, all overexpressing human -synuclein, followed by determination of the cryo-EM structures of the seeded filaments. Whereas MSA seeds comprise two protofilaments with an unidentified non-proteinaceous density located between protofilaments, seeding resulted in the formation of filaments with a single protofilament. Only the seeded structures derived from oligodendrocytes contained an extra density that resembled that of the seeds. This suggests that oligodendrocytes may provide the chemical component that is responsible for the extra density at the protofilament interface of MSA filaments. In support, the injection of MSA seeds into the striatum of transgenic mice expressing human -synuclein under the control of the oligodendrocyte-specific proteolipid protein promoter, also yielded seeded filaments with a single protofilament and a similar extra density.

neuroscience↗

bioRxiv2026

Prion-like transmission of human tau strains in the mouse brain

Most neurodegenerative diseases are believed to spread through the brain by prion-like mechanisms, where filamentous protein assemblies self-propagate by templated seeding 1. Distinct conformations of amyloid filaments are thought to provide the physical basis for the strains that lead to different diseases 2. However, a central pillar of the prion hypothesis, that strains retain their structural identity upon transmission, has not been demonstrated. Here we show that the injection of tau filaments from the brains of individuals with Alzheimers disease or corticobasal degeneration into the brains of wildtype mice leads to the seeded assembly of amyloid filaments made of mouse tau with the same structures as those of the seeds. Thereby, we establish that, like prion strains, tau filaments propagate through templated seeding, and that the mouse is a suitable model to study the molecular mechanisms by which distinct tau folds drive disease-specific pathology in the brain.

neuroscience↗

bioRxiv2023

Cryo-EM structures of tau filaments from SH-SY5Y cells seeded with brain extracts from cases of Alzheimer's disease and corticobasal degeneration

The formation of amyloid filaments through templated seeding is believed to underlie the propagation of pathology in most human neurodegenerative diseases. A widely used model system to study this process is to seed amyloid filament formation in cultured cells using human brain extracts. Here, we report the electron cryo-microscopy (cryo-EM) structures of tau filaments from undifferentiated seeded SH-SY5Y cells, that transiently expressed N-terminally HA-tagged 1N3R or 1N4R human tau, using brain extracts from individuals with AD or CBD. Although the resulting filament structures differed from those of the brain seeds, some degree of structural templating was observed. Studying templated seeding in cultured cells, and determining the structures of the resulting filaments, can thus provide insights into the cellular aspects underlying neurodegenerative diseases.

neuroscience↗

bioRxiv2021

Age-dependent formation of TMEM106B amyloid filaments in human brain

Many age-dependent neurodegenerative diseases, like Alzheimers and Parkinsons, are characterised by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-{beta} (A{beta}), -synuclein and TDP-43 are the most common. Here, we used electron cryo-microscopy (cryo-EM) structure determination to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in the human brain. We solved cryo-EM structures of TMEM106B filaments from the brains of 22 individuals with neurodegenerative conditions, including sporadic and inherited tauopathies, A{beta}-amyloidoses, synucleinopathies and TDP-43opathies, as well as from the brains of two neurologically normal individuals. We observed three different TMEM106B folds, with no clear relationship between folds and diseases. The presence of TMEM106B filaments correlated with that of a 29 kDa sarkosyl-insoluble fragment of the protein on Western blots. The presence of TMEM106B filaments in the brains of older, but not younger, neurologically normal individuals indicates that they form in an age-dependent manner.

neuroscience↗

bioRxiv2021

Peptide-based inhibitors of Tau aggregation as a potential therapeutic for Alzheimer's disease and other Tauopathies

There are currently no disease altering drugs available for Tauopathies such as Alzheimers disease, which alone is predicted to affect ~88 million people worldwide by 2050. As Tau aggregation underpins its toxicity, aggregation inhibitors are likely to have disease-modifying potential. Guided by in-silico mutagenesis studies, we developed a potent retro-inverso peptide inhibitor of Tau aggregation, RI-AG03 [Ac-rrrrrrrrGpkyk(ac)iqvGr-NH2], based on the 306VQIVYK311 hotspot. Aggregation of recombinant Tau was reduced by >90% with equimolar RI-AG03 and no fibrils were observed by EM. When added during the growth phase, RI-AG03 blocked seeded aggregation. Fluorescein-tagged RI-AG03 efficiently penetrated HEK-293 cells over 24 hours and was non-toxic at doses up to 30 M. In transgenic Drosophila, RI-AG03 significantly improves neurodegenerative and behavioural phenotypes caused by expression of human Tau. Collectively this shows that RI-AG03 can effectively reduce Tau aggregation in vitro and block aggregation-dependent phenotypes in vivo, raising possibilities for exploring its translational potential.

neuroscience↗

bioRxiv2021

Structure-based Classification of Tauopathies

Ordered assembly of the tau protein into filaments characterizes multiple neurodegenerative diseases, which are called tauopathies. We previously reported that by electron cryo-microscopy (cryo-EM), tau filament structures from Alzheimers disease (1,2), chronic traumatic encephalopathy (CTE) (3), Picks disease (4) and corticobasal degeneration (CBD) (5) are distinct. Here we show that the structures of tau filaments from typical and atypical progressive supranuclear palsy (PSP), the most common tauopathy after Alzheimers disease, define a previously unknown, three-layered fold. Moreover, the tau filament structures from globular glial tauopathy (GGT, Types I and II) are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs from the above and resembles the four-layered CBD fold. The majority of tau filaments from aging-related tau astrogliopathy (ARTAG) also have the AGD fold. Surprisingly, tau protofilament structures from inherited cases with mutations +3/+16 in intron 10 of MAPT, the microtubule-associated protein tau gene, are identical to those from AGD, suggesting that a relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, tau filament structures from cases of familial British dementia (FBD) and familial Danish dementia (FDD) are the same as those from Alzheimers disease and primary age-related tauopathy (PART). These structures provide the basis for a classification of tauopathies that also allows identification of new entities, as we show here for a case diagnosed as PSP, but with abundant spherical 4R tau inclusions in limbic and other brain areas. The structures of the tau fold of this new disease (Limbic-predominant Neuronal inclusion body 4R Tauopathy, LNT) were intermediate between those of GGT and PSP.

neuroscience↗

bioRxiv2020

Seeded assembly in vitro does not replicate the structures of α-synuclein filaments from multiple system atrophy

The propagation of conformational strains by templated seeding is central to the prion concept. Seeded assembly of -synuclein into filaments is believed to underlie the prion-like spreading of protein inclusions in a number of human neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We previously determined the atomic structures of -synuclein filaments from the putamen of five individuals with MSA. Here, we used filament preparations from three of these brains for the in vitro seeded assembly of recombinant human -synuclein. We find that the structures of the seeded assemblies differ from those of the seeds, suggesting that additional, as yet unknown, factors play a role in the propagation of pathology. Identification of these factors will be essential for understanding the prion-like spreading of -synuclein proteinopathies.

molecular biology↗

bioRxiv2020

Structures of α-synuclein filaments from multiple system atrophy

Synucleinopathies are human neurodegenerative diseases that include multiple system atrophy (MSA), Parkinsons disease, Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB) (1). Existing treatments are at best symptomatic. These diseases are characterised by the presence in brain cells of filamentous inclusions of -synuclein, the formation of which is believed to cause disease (2, 3). However, the structures of -synuclein filaments from human brain are not known. Here we show, using electron cryo-microscopy, that -synuclein inclusions from MSA are made of two types of filaments, each of which consists of two different protofilaments. Non-proteinaceous molecules are present at the protofilament interfaces. By two-dimensional class averaging, we show that -synuclein filaments from the brains of patients with MSA and DLB are different, suggesting that distinct conformers (or strains) characterise synucleinopathies. As was the case of tau assemblies (4-9), the structures of -synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, with implications for understanding the mechanisms of aggregate propagation and neurodegeneration in human brain. These findings have diagnostic and potential therapeutic relevance, especially in view of the unmet clinical need to be able to image filamentous -synuclein inclusions in human brain.

neuroscience↗

bioRxiv2019

Novel tau filament fold in corticobasal degeneration, a four-repeat tauopathy

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 Picks disease, filaments of which are made of three-repeat (3R) tau isoforms, and from Alzheimers 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 Alzheimers disease, Picks 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.

neuroscience↗