Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids

Nature, Journal Year: 2023, Volume and Issue: 621(7980), P. 701 - 710

Published: Sept. 27, 2023

Language: Английский

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TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP

Nature, Journal Year: 2023, Volume and Issue: 620(7975), P. 898 - 903

Published: Aug. 2, 2023

Abstract The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases amyotrophic lateral sclerosis (ALS) around half frontotemporal lobar degeneration (FTLD) 1,2 . A causal role for TDP-43 neurodegeneration is evidenced by dominantly inherited missense mutations TARDBP , the gene encoding TDP-43, that promote give rise to ALS FTLD 3–7 At least four types (A–D) with pathology (FTLD-TDP) are defined distinct brain distributions assembled associated different clinical presentations dementia 8 We previously showed, using cryo-electron microscopy, assembles into amyloid filaments type B FTLD-TDP 9 However, structures without remained unknown. Here we report microscopy from brains three individuals most common FTLD-TDP, A. formed a new fold was same across individuals, indicating this may characterize FTLD-TDP. resembles chevron badge unlike double-spiral-shaped establishing filament folds neurodegenerative conditions. structures, combination mass spectrometry, led identification two post-translational modifications citrullination monomethylation R293, indicate they facilitate formation observed structural variation individual filaments. will guide mechanistic studies assembly, as well development diagnostic therapeutic compounds proteinopathies.

Language: Английский

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Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: Dec. 7, 2023

The abnormal aggregation and accumulation of alpha-synuclein (aSyn) in the brain is a defining hallmark synucleinopathies. Various aSyn conformations post-translationally modified forms accumulate pathological inclusions vary abundance among these disorders. Relying on antibodies that have not been assessed for their ability to detect diverse may lead inaccurate estimations pathology human brains or disease models. To address this challenge, we developed characterized an expanded antibody panel targets different sequences post-translational modifications along length aSyn, recognizes all monomeric, oligomeric, fibrillar conformations. Next, profiled across sporadic familial Lewy body diseases (LBDs) reveal heterogeneous pathology, rich Serine 129 phosphorylation, Tyrosine 39 nitration N- C-terminal tyrosine phosphorylations, scattered both neurons glia. In addition, show can become hyperphosphorylated during processes inclusion maturation neuronal animal models seeding spreading. validation pipeline describe paves way systematic investigations into diversity brain, peripheral tissues, as well cellular

Language: Английский

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Cryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 12, 2024

Abstract The transactive response DNA-binding protein-43 (TDP-43) is a multi-facet protein involved in phase separation, RNA-binding, and alternative splicing. In the context of neurodegenerative diseases, abnormal aggregation TDP-43 has been linked to amyotrophic lateral sclerosis frontotemporal lobar degeneration through its C-terminal domain. Here, we report cryo-electron microscopy (cryo-EM)-based structural characterization fibrils obtained from full-length protein. We find that are polymorphic contain three different amyloid structures. structures differ number relative orientation protofilaments, although they share similar fold containing an key motif. observed fibril previously described conformations help better understand landscape derived this

Language: Английский

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Local structural preferences in shaping tau amyloid polymorphism

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 3, 2024

Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, extent to which intrinsic structural tendencies cores contribute remains uncertain. Using combination experimental approaches, we here identify new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif Repeat 4), as significant contributor polymorphism. Calculation per-residue contributions stability different pathologic structures plays central role in preserving integrity polymorphs. Consistent with this, cryo-EM analysis fibrils formed from synthetic peptide shows sequence adopts alternative closely correspond disease-associated strains. Furthermore, in-cell experiments revealed deletion hampers cellular seeding efficiency aggregates extracted Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal these tauopathies. Together, our results highlight importance propensity core segments determine structure cells, propagating

Language: Английский

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Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 141677 - 141677

Published: March 1, 2025

Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding involved in various cellular processes, including RNA splicing, transcription regulation, and stability. Mislocalization aggregation of TDP-43 the cytoplasm are key features pathogenesis several neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD). This review provides comprehensive retrospective prospective analysis research, highlighting structural insights, significant milestones, evolving understanding its physiological pathological functions. We delineate five major stages from initial discovery as hallmark neurodegeneration to recent advances liquid-liquid phase separation (LLPS) behavior interactions with processes. Furthermore, we assess therapeutic strategies targeting pathology, categorizing approaches into direct indirect interventions, alongside modulating aberrant LLPS. propose that future research will focus on three areas: polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation TDP-43, advancing nano-therapy. More importantly, emphasize importance TDP-43's functional repertoire at mesoscale, which bridges molecular functions broader offers foundational framework development.

Language: Английский

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Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy

The Lancet Neurology, Journal Year: 2025, Volume and Issue: 24(5), P. 456 - 470

Published: April 16, 2025

Language: Английский

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Involvement of CB1 and CB2 receptors in neuroprotective effects of cannabinoids in experimental TDP-43 related frontotemporal dementia using male mice

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 174, P. 116473 - 116473

Published: March 24, 2024

The elevation of endocannabinoid levels through inhibiting their degradation afforded neuroprotection in CaMKIIα-TDP-43 mice, a conditional transgenic model frontotemporal dementia. However, which cannabinoid receptors are mediating these benefits is still pending to be elucidated. We have investigated the involvement CB1 and CB2 receptor using chronic treatments with selective ligands analysis cognitive deterioration Novel Object Recognition test, immunostaining for neuronal glial markers two areas interest Our results confirmed therapeutic value activating either or receptor, improvements animal performance preservation pyramidal neurons, particular medial prefrontal cortex, attenuation reactivity, hippocampus. In addition, activation both reduced elevated TDP-43 cortex an effect exerted by mechanisms that currently under investigation. These data reinforce notion may represent promising therapy against TDP-43-induced neuropathology Future studies will confirm benefits, one agonists used here, has been thoroughly characterized clinical development.

Language: Английский

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Mutations in human prion-like domains: pathogenic but not always amyloidogenic

Prion, Journal Year: 2024, Volume and Issue: 18(1), P. 28 - 39

Published: March 21, 2024

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are multifunctional proteins with integral roles in RNA metabolism and the regulation of alternative splicing. These typically contain prion-like domains low complexity (PrLDs or LCDs) that govern their assembly into either functional pathological amyloid fibrils. To date, over 60 mutations targeting LCDs hnRNPs have been identified associated a spectrum neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD). The cryo-EM structures fibrils formed by different recently elucidated, those hnRNPA1, hnRNPA2, hnRNPDL-2, TDP-43, FUS. In this review, we discuss structural features these assemblies, placing particular emphasis on scrutinizing impact prevalent disease-associated mapping within LCDs. By performing systematic energy calculations, reveal prevailing trend destabilizing effects induced structure, challenging traditionally assumed correlation between pathogenicity amyloidogenic propensity. Understanding molecular basis discrepancy might provide insights for developing targeted therapeutic strategies to combat hnRNP-associated diseases.

Language: Английский

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Small heat shock protein HSPB8 interacts with a pre-fibrillar TDP43 low complexity domain species to delay fibril formation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

The loss of cellular proteostasis through aberrant stress granule formation is implicated in neurodegenerative diseases. Stress granules are formed by biomolecular condensation involving protein-protein and protein-RNA interactions. These assemblies protective, but can rigidify, leading to amyloid-like fibril formation, a hallmark the disease pathology. Key proteins dictating disassembly, such as TDP43, contain low-complexity (LC) domains that drive formation. HSPB8, small heat shock protein, plays critical role modulating fluidity, preventing aggregation promoting degradation misfolded proteins. We examined interaction between HSPB8 TDP43 LC using thioflavin T (ThT) fluorescence polarization (FP) assays, microscopy photobleaching experiments, crosslinking mass spectrometry (XL-MS). Our results indicate delays domain-specific interactions with nucleating species, without affecting elongation rates. findings provide mechanistic insight into how ATP-independent chaperones mediate domain basis for investigating subverts chaperone activity disease. facilitate clearance aggregated autophagy. This study provides molecular mechanism which interact aggregation-prone low complexity protein RNA-binding linked pathologies. foundation designing improved therapeutics illustrate methodology identify regions targeted drug development context

Language: Английский

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