Biology subjects

Vidal, R.

Publications and source records attributed to Vidal, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Unveiling the intraspecific genomic diversity of South American lowland maize landraces

Abstract Background and Aims South American Lowland maize landraces constitute an important reservoir of the species diversity, although research regarding the territories of Uruguay and Brazil remains comparatively unexplored. This study aimed to evaluate the intragenomic variability of maize landraces from Uruguay and Brazil. Methods We estimated the genome size, number of heterochromatic knobs, and presence of B chromosomes in 15 maize landraces representing 13 races, and finally, we conducted an analysis of repetitive sequences in landraces from both countries. Key Results Regarding DNA content, a north-to-south gradient of decreasing genome size was found, significantly associated with latitude. At the knob level, a model incorporating the Country x Race interaction detected significant effects, revealing a reversal of the pattern of knob number per race among countries. B chromosomes were found only in Uruguayan races, whereas regarding repetitive sequences, a trend of increasing retrotransposons and decreasing knobs was observed as DNA content decreased. Conclusions Taken together, these results suggest that genome size may be influenced by selective pressures associated with local adaptation, although further investigation is needed to test this hypothesis. Furthermore, the knob profiles of specific races across countries, as well as the presence of B chromosomes in Uruguay, may reflect distinct histories of dispersal, local selection, and even introgression, highlighting the complexity of the processes shaping maize genomic architecture across geographic gradients.

genetics↗

bioRxiv2026

Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease

Tau is a microtubule-associated protein with diverse roles in the healthy brain but contributes to neurodegenerative disorders when dysregulated. Although tau ablation has shown protective effects in several disease models, how its absence confers this protection remain unclear. Here, we performed and analyzed single-nucleus RNA sequencing on cortices of aged tau knockout (Mapt-/-) mice in a wild type background as well as in a vascular amyloid model to evaluate the effect on disease context. Comparisons in a wild type setting revealed that tau ablation induced compensatory remodeling across multiple cell types. Excitatory neurons expanded into a distinct subtype with unique glutamatergic signaling, astrocytes adopted synaptoprotective states, oligodendrocytes upregulated genes supporting connectivity and plasticity, and microglia engaged structural remodeling programs. In contrast, in disease, tau removal not only restored functions disrupted by vascular amyloid pathology, but also generated new phenotypes. Excitatory neurons rewired receptor and postsynaptic signaling, astrocytes and oligodendrocytes recovered wild-type-like gene programs related to neurotransmitter cycling, synaptic support, and myelin integrity, and microglia reprogrammed toward sensing and mounting responses. Together, these findings demonstrate that tau ablation reshapes brain cellular programs in a context-dependent manner, exerting adaptive responses in the otherwise healthy brain while restoring homeostatic functions under vascular amyloid pathology. These results position tau as a key regulator of neuronal-glial network balance and highlight the importance of understanding how tau influences distinct cellular programs within specific disease environments.

neuroscience↗

bioRxiv2026

TREM2 deficiency causes region-specific brain effects in a mouse model of cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA), a major vascular contributor to cognitive decline, is present in 85-95% of Alzheimers disease (AD) patients. Despite its high prevalence, the mechanisms by which CAA contributes to neurodegeneration remain poorly understood. Triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor expressed exclusively by microglia, regulates activation, phagocytosis, and amyloid clearance, thereby shaping neuroinflammation. Loss-of-function mutations in TREM2 markedly increase AD risk, but its role in CAA pathology remains unknown. To investigate this, we crossed the Familial Danish Dementia (Tg-FDD) mouse model, which accumulates robust vascular amyloid, with TREM2 knockout (TREM2KO) mice to generate Tg-FDD/TREM2KO animals. Histological and transcriptomic analyses revealed region-specific effects of TREM2 deficiency. In the cortex, TREM2 loss markedly reduced vascular amyloid deposition, accompanied by decreased tau pathology. In contrast, in the cerebellum, TREM2 deletion exacerbated vascular amyloid accumulation, promoted astrogliosis, and enhanced tau pathology. Transcriptomic profiling further identified distinct neuroinflammatory signatures between cortex and cerebellum, particularly in cytokine signaling, matrix remodeling, and lipid metabolism. Together, these findings demonstrate that TREM2 deficiency leads to region-specific effects on CAA, revealing extensive regional variability in vascular amyloid pathology and underscoring the importance of considering these differences when developing TREM2-based therapies.

neuroscience↗

bioRxiv2025

Transcriptional stress induces the overexpression of novel lncRNAs that regulate the BRCA1 locus

BackgroundRegulation of gene transcription is an essential early response to a broad variety of cellular stress. Paradoxically, pharmacological inhibition of an RNA polymerase II transcription initiation factor, XPB, induces a stress response that overactivates transcription of a subset of transcripts, including lncRNAs. However, the mechanisms enabling selective transcription under global initiation blockade, and the regulatory contribution of lncRNAs, remain unclear. ResultsGenome-wide assays in human cells treated with triptolide, which disrupts XPB translocase activity within TFIIH, revealed that a subset of genes continues to be transcribed independently of XPB activity, driven by thermodynamically unstable promoters. These promoters account for paradoxical transcriptional upregulation during global transcriptional inhibition. Among XPB-resistant transcripts, we identified previously uncharacterized regulatory long non-coding RNAs--TILR-1, TILR-2, and LINC00910--that are conserved in primates and display interdependent expression. Together, these lncRNAs form a coordinated regulatory module that modulates transcription at the BRCA1 locus. Disruption of expression of these lncRNAs promotes cell proliferation and survival, phenocopying reduced expression of BRCA1 locus genes. This lncRNA network is also activated by distinct transcriptional inhibitors indicating a shared transcriptional stress-responsive mechanism. ConclusionsUnstable promoters sustain transcription in the absence of XPB, defining an XPB-independent transcriptional program that includes a transcriptional stress-responsive lncRNA regulatory network. This mechanism enables selective gene activation during global transcriptional inhibition, with the BRCA1 locus representing one example, and suggests a broader transcriptional switch involved in cellular adaptation to transcriptional stress.

molecular biology↗

bioRxiv2025

Mapping brain function underlying naturalistic motor observation and imitation using high-density diffuse optical tomography

BackgroundAutism spectrum disorder (ASD), a condition defined by deficits in social communication, restricted interests, and repetitive behaviors, is associated with early impairments in motor imitation that persist through childhood and into adulthood. Alterations in the mirror neuron system (MNS), crucial for interpreting and imitating actions, may underlie these ASD-associated differences in motor imitation. High-density diffuse optical tomography (HD-DOT) overcomes logistical challenges of functional magnetic resonance imaging to enable identification of neural substrates of naturalistic motor imitation. ObjectiveWe aim to investigate brain function underlying motor observation and imitation in autistic and non-autistic adults. We hypothesize that HD-DOT will reveal greater activation in regions associated with the MNS during motor imitation than motor observation, and that MNS activity will negatively correlate with autistic traits and motor fidelity. MethodsWe imaged brain function using HD-DOT in N = 100 participants as they engaged in observing or imitating a sequence of arm movements. Additionally, during imitation, participant movements were simultaneously recorded with 3D cameras for computer-vision-based assessment of motor imitation (CAMI). Cortical responses were estimated using general linear models, and multiple regression was used to test for associations with autistic traits, assessed via the Social Responsiveness Scale-2 (SRS), and imitation fidelity, assessed via CAMI. ResultsBoth observing and imitating motor movements elicited significant activations in higher-order visual and MNS regions, including the inferior parietal lobule, superior temporal gyrus, and inferior frontal gyrus. Imitation additionally exhibited greater activation in the superior parietal lobule, primary motor cortex, and supplementary motor area. Notably, the right temporal-parietal junction exhibited activation during observation but not during imitation. Higher autistic traits were associated with increased activation during motor observation in the right superior parietal lobule. No significant correlation between brain activation and CAMI scores was observed. ConclusionsOur findings provide robust evidence of shared and task-specific cortical responses underlying motor observation and imitation, emphasizing the differential engagement of MNS regions during motor observation and imitation.

neuroscience↗

bioRxiv2025

The MYCN/Aurora-A complex is a cyclin activating kinase for CDK12

Deregulated MYCN is a driver of aggressive pediatric and adult neuroendocrine tumors, but critical oncogenic processes downstream of MYCN remain poorly defined. In neuroblastoma, MYCN interacts with and activates the Aurora-A kinase. Here we show that Aurora-A is a CDK-activating kinase for CDK12 by phosphorylating T893 in the T-loop, thereby enhancing its kinase activity. Aurora-A-dependent activation of CDK12 controls phosphorylation of T4 of RNA polymerase and recruits transcription termination complexes, thereby preventing transcription-replication conflicts. Enhanced crosslinking and immunoprecipitation sequencing reveals that Aurora-A associates with splice sites on nascent RNA. RNA-bound Aurora-A is catalytically inactive. MYCN competes with RNA for binding to Aurora-A and displaces Aurora-A from RNA in cells, promoting its CDK12 kinase activity. Combining Aurora-A and CDK12 inhibition potently suppresses the growth of MYCN-amplified neuroblastoma cells and patient-derived xenografts. Our data demonstrate that an Aurora-A/CDK12-dependent transcription termination pathway is a critical and targetable dependency of MYCN-driven tumors.

cancer biology↗

bioRxiv2024

Persistence phenotype of adherent-invasive Escherichia coli in response to ciprofloxacin, revealing high-persistence strains

Persister cells correspond to a bacteria subpopulation able to survive antibiotic treatments and are thought to contribute to chronicity and symptom relapse of chronic diseases. Crohns disease (CD) is a multifactorial chronic inflammatory condition of the gastrointestinal tract, and adherent-invasive Escherichia coli (AIEC) has emerged as a key contributor to its pathogenesis. AIEC can survive, replicate, and produce persister cells within macrophages; however, out of the LF82 reference strain, a lack of knowledge of the persistence phenotype and its variability among AIEC strains is lacking. Here, two AIEC reference strains were analyzed after ciprofloxacin challenge, a fluoroquinolone antibiotic common in CD treatments. Four clinical isolates with an AIEC phenotype and five different E. coli pathotypes were also analyzed. We investigated the roles of the resident antibiotic resistance plasmid and the stress response protein HtrA, along with macrophage-induced persister formation. We observed a broad variability of persister cell formation capability among AIEC strains. Remarkably, the reference NRG857c strain showed a threatening high-persistence phenotype, with persistence levels higher than LF82 (65-fold) and some AIEC clinical isolates. The resident antibiotic resistance plasmid and the stress protein HtrA were dispensable for the NRG857c persistence phenotype. Among E. coli pathotypes, only EPEC showed persistence levels comparable to NRG857c, while other pathotypes resembled the lower persistence levels of LF82. Macrophage internalization did not increase NRG857c persister fraction, opposite to the LF82 behavior. Overall, our findings show that variable persistence phenotypes are found among AIEC. Opposite to LF82, NRG857c is a high-persistence strain, and this characteristic is shared with one AIEC clinical isolated and the EPEC reference strain. Undoubtedly, bacterial persistence should be considered in CD antibiotic treatments, especially with the feasible presence of AIEC high-persistence strains. Author SummaryAdherent-invasive Escherichia coli (AIEC) are common bacteria found in Crohns disease patients and recognized to survive within macrophages. The reference strain LF82 is known to form persistent cells, an enigmatic subpopulation of cells able to survive antibiotic treatments and thought to contribute to chronicity and symptoms relapses of chronic diseases. However, out of LF82, there is a lack of knowledge on AIEC persister cell formation, as well as the genetic factors contributing to this phenotype. In this study, it was observed a that the persistence phenotype was variable among both AIEC strains and E. coli pathotypes. Unlike LF82, the reference strain NRG857c displayed inherently high-persistence levels, regardless of whether it carries its native antibiotic resistance plasmid or the htrA and hipA genes. Notably, stress conditions within macrophages did not trigger increased persister cell formation in NRG857c. This study highlights the importance to decipher the role of AIEC persisters in ongoing Crohns disease, symptom relapses, and responses to antibiotic treatment, especially given the potential existence of high-persistence AIEC strains.

microbiology↗

bioRxiv2024

Novel tau filament folds in individuals with MAPT mutations P301L and P301T

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 Picks 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.

neuroscience↗

bioRxiv2024

A trimeric USP11/USP7/TCEAL1 complex stabilizes RNAPII during early transcription to sustain oncogenic gene expression

During early transcription, RNA polymerase II (RNAPII) undergoes a series of structural transitions controlled by cyclin-dependent kinases. Whether protein ubiquitylation and proteasomal degradation affect the fate of RNAPII close to promoters is less well understood. Here we show that the deubiquitylating enzyme USP11 and its heterodimeric partner USP7 form a trimeric complex with TCEAL1, a member of the poorly understood TCEAL (TCEA/TFIIS-like) protein family. TCEAL1 shares sequence homology with the RNAPII interaction domain of the TCEA/TFIIS elongation factor, which controls the fate of backtracked RNAPII. TCEAL1 stabilizes complexes of USP11 with USP7 and with RNAPII. TCEAL1 is recruited to core promoters when transcription elongation is blocked and globally enhances the chromatin association of RNAPII during early transcription. Mechanistically, the USP11/USP7/TCEAL1 complex competes with TFIIS for binding to core promoters and protects RPB8, an essential subunit of RNAPII, from degradation, likely preventing excessive TFIIS-mediated transcript cleavage and RNAPII disassembly. In neuroblastoma and other tumors, TCEAL1-dependent genes define a TGF beta-dependent gene expression program that is characteristic for mesenchymal and invasive tumor cell types, suggesting that the USP11/USP7/TCEAL1 trimer stabilizes RNAPII during early transcription to support a critical oncogenic gene expression program (190 words).

cancer biology↗

bioRxiv2024

Phosphorylation at serine 214 correlates with tau seeding activity in an age-dependent manner in two mouse models for tauopathies and is required for tau transsynaptic propagation.

Pathological aggregation and propagation of hyperphosphorylated and aberrant forms of tau are critical features of the clinical progression of Alzheimers disease and other tauopathies. To better understand the correlation between these pathological tau species and disease progression, we profiled the temporal progression of tau seeding activity and the levels of various phospho- and conformational tau species in the brains of two mouse models of human tauopathies. Our findings indicate that tau seeding is an early event that occurs well before the appearance of AT8-positive NFT. Specifically, we observed that tau phosphorylation in serine 214 (pTau-Ser214) positively correlates to tau seeding activity during disease progression in both mouse models. Furthermore, we found that the histopathology of pTau-Ser214 appears much earlier and has a distinct pattern and compartmentalization compared to the pathology of AT8, demonstrating the diversity of tau species within the same region of the brain. Importantly, we also observed that preventing the phosphorylation of tau at Ser214 significantly decreases tau propagation in mouse primary neurons, and seeding activity in a Drosophila model of tauopathy, suggesting a role for this tau phosphorylation in spreading pathological forms of tau. Together, these results suggest that the diverse spectrum of soluble pathological tau species could be responsible for the distinct pathological properties of tau and that it is critical to dissect the nature of the tau seed in the context of disease progression.

neuroscience↗

bioRxiv2024

Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C

Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system1. Human genetic studies 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 electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains1. All diseases studied to date have been characterised by the self-assembly of a single intracellular protein 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-EM 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 G282/284-N345 and ANXA11 residues L39-L74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 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 a [~]22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections confirmed the co-localisation 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 human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Brain and cancer associated binding domain mutations provide insight into CTCF's relationship with chromatin and its ability to act as a chromatin organizer

Here we used a series of CTCF mutations to explore CTCFs relationship with chromatin and its contribution to gene regulation. CTCFs impact depends on the genomic context of bound sites and the unique binding properties of WT and mutant CTCF proteins. Specifically, CTCFs signal strength is linked to changes in accessibility, and the ability to block cohesin is linked to its binding stability. Multivariate modelling reveals that both CTCF and accessibility contribute independently to cohesin binding and insulation, however CTCF signal strength has a stronger effect. CTCF and chromatin have a bidirectional relationship such that at CTCF sites, accessibility is reduced in a cohesin-dependent, mutant specific fashion. In addition, each mutant alters TF binding and accessibility in an indirect manner, changes which impart the most influence on rewiring transcriptional networks and the cells ability to differentiate. Collectively, the mutant perturbations provide a rich resource for determining CTCFs site-specific effects.

molecular biology↗

bioRxiv2023

Association with TFIIIC limits MYCN localization in hubs of active promoters and chromatin accumulation of non-phosphorylated RNA Polymerase II

MYC family oncoproteins regulate the expression of a large number of genes and broadly stimulate elongation by RNA polymerase II. While the factors that control the chromatin association of MYC proteins are well understood, much less is known about how interacting proteins mediate MYCs effects on transcription. Here we show that TFIIIC, an architectural protein complex that controls the three-dimensional chromatin organization at its target sites, binds directly to the amino-terminal transcriptional regulatory domain of MYCN. Surprisingly, TFIIIC has no discernible role in MYCN-dependent gene expression and transcription elongation. Instead, MYCN and TFIIIC preferentially bind to promoters with paused RNAPII and globally limit the accumulation of non-phosphorylated RNAPII at promoters. Consistent with its ubiquitous role in transcription, MYCN broadly participates in hubs of active promoters. Depletion of TFIIIC further increases MYCN localization to these hubs. This increase correlates with a failure of the nuclear exosome and BRCA1, both of which are involved in nascent RNA degradation, to localize to active promoters. Our data suggest that MYCN and TFIIIC exert an censoring function in early transcription that limits promoter accumulation of inactive RNAPII and facilitates promoter-proximal degradation of nascent RNA.

molecular biology↗

bioRxiv2023

Cross-β helical filaments of Tau and TMEM106B in Gray and White Matter of Multiple System Tauopathy with presenile Dementia

BackgroundThe Microtubule-Associated Protein Tau (MAPT) is one of the proteins that are central to neurodegenerative diseases. The nature of intracellular tau aggregates is determined by the cell types whether neuronal or glial, the participating tau isoforms, and the structure of the amyloid filament. The transmembrane protein 106B (TMEM106B) has recently emerged as another significant player in neurodegeneration and aging. In the central nervous system, the composition of the gray and white matter differs considerably. The gray matter consists of nerve cell bodies, dendrites, unmyelinated axons, synaptic terminals, astrocytes, oligodendrocytes (satellite cells) and microglia. The white matter differs from the gray for the presence of axonal tracts as the only neuronal component and for the absence of nerve cell bodies, dendrites and synaptic terminals. Cryogenic electron microscopy (cryo-EM) studies have unveiled the structure of tau and TMEM106B, from the cerebral cortex, in several neurodegenerative diseases; however, whether tau and TMEM106B filaments from the gray and white matter share a common fold requires additional investigation. MethodsWe isolated tau and TMEM106B from the cerebral cortex and white matter of the frontal lobes of two individuals affected by multiple system tauopathy with presenile dementia (MSTD), a disease caused by the MAPT intron 10 mutation +3. We used immunostaining, biochemical, genetics and cryo-EM methods to characterize tau and TMEM106B. ResultsWe determined that tau filaments in the gray and the white matter of MSTD individuals can induce tau aggregation and have identical AGD type 2 folds. TMEM106B amyloid filaments were also found in the gray and white matter of MSTD; the filament folds were identical in the two anatomical regions. ConclusionsOur findings show for the first time that in MSTD two types of amyloid filaments extracted from the gray matter have identical folds to those extracted from the white matter. Whether in this genetic disorder there is a relationship in the pathogenesis of the tau and TMEM106B filaments, remains to be determined. Furthermore, additional studies are needed for other proteins and other neurodegenerative diseases to establish whether filaments extracted from the gray and white matter would have identical folds.

neuroscience↗

bioRxiv2022

New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy

A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant -synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). Both wild-type -synuclein and its insertion mutant containing seven additional residues (MAAAEKT) after residue 22 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 -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 -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. Our findings provide insight into a likely mechanism of JOS fibrillation in which mutant -synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.

neuroscience↗

bioRxiv2022

Cryo-EM structures of α-synuclein filaments from Parkinson's disease and dementia with Lewy bodies

Parkinsons disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms (1). Neuropathologically, it is characterised by the presence of abundant filamentous inclusions of -synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra (2). PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis (3). PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset (4). In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy (5). It is characterised by the presence of abundant filamentous -synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy (cryo-EM) structures of two types of -synuclein filaments extracted from the brains of individuals with MSA (6). Each filament type is made of two different protofilaments. Here we report that the cryo-EM structures of -synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled -synuclein in neurodegenerative disease.

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

Cryo-EM Structures of Amyloid-β 42 Filaments from Human Brain

Filament assembly of amyloid-{beta} peptides ending at residue 42 (A{beta}42) is a central event in Alzheimers disease. We report the cryo-EM structures of A{beta}42 filaments from brain. 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 Alzheimers disease and Type II filaments in individuals with familial Alzheimers disease and other conditions. The structures of A{beta}42 filaments from brain differ from those of filaments assembled in vitro. By contrast, in AppNL-F knock-in mice, A{beta}42 deposits were made of Type II filaments. Knowledge of A{beta}42 filament structures from human brain may lead to the development of inhibitors of assembly and improved imaging agents.

neuroscience↗