FTLD‐TDP assemblies seed neoaggregates with subtype‐specific features via a prion‐like cascade

Rossi, Pierre De; Blythe, Amanda; Furrer, Johanna; Vos, Laura De; Demeter, Tomas; Zbinden, Aurélie; Weijia, Zhong; Wiersma, Vera I.; Scialò, Carlo; Weber, Julien; Guo, Zhongning; Scaramuzza, Stefano; Fabrizio, Marta Di; Böing, Carolin; Castaño-Díez, Daniel; Al‐Amoudi, Ashraf; Pérez‐Berlanga, Manuela; Lashley, Tammaryn; Stahlberg, Henning; Polymenidou, Magdalini

doi:10.15252/embr.202153877

Cited by 18 publications

(31 citation statements)

References 74 publications

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“…Furthermore, the insoluble fractions extracted from the cells into which patient-derived TDP-43 seeds had been introduced showed CTF banding patterns similar to those of the patient-derived original seeds [ 217 ]. Insoluble TDP-43 extracted from FTLD-TDP type A-C cases by Sarkospin also shows differences of cytotoxicity and seeding activity in cultured cells depending on the subtype [ 79 , 176 ]. In addition, it has been reported that insoluble TDP-43 extracted from ALS cases induces the formation of phosphorylated TDP-43 inclusions with various morphologies, as observed in the brain of ALS patients in cultured cells expressing wild-type TDP-43, and that the prion-like property of insoluble TDP-43 accumulated in cultured cells is inherited after passaging of the cells [ 269 ].…”

Section: Experimental Prion-like Amplification and Transmission Of Pa...mentioning

confidence: 99%

Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43

et al. 2022

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Intracellular accumulation of abnormal proteins with conformational changes is the defining neuropathological feature of neurodegenerative diseases. The pathogenic proteins that accumulate in patients' brains adopt an amyloid-like fibrous structure and exhibit various ultrastructural features. The biochemical analysis of pathogenic proteins in sarkosyl-insoluble fractions extracted from patients’ brains also shows disease-specific features. Intriguingly, these ultrastructural and biochemical features are common within the same disease group. These differences among the pathogenic proteins extracted from patients’ brains have important implications for definitive diagnosis of the disease, and also suggest the existence of pathogenic protein strains that contribute to the heterogeneity of pathogenesis in neurodegenerative diseases. Recent experimental evidence has shown that prion-like propagation of these pathogenic proteins from host cells to recipient cells underlies the onset and progression of neurodegenerative diseases. The reproduction of the pathological features that characterize each disease in cellular and animal models of prion-like propagation also implies that the structural differences in the pathogenic proteins are inherited in a prion-like manner. In this review, we summarize the ultrastructural and biochemical features of pathogenic proteins extracted from the brains of patients with neurodegenerative diseases that accumulate abnormal forms of tau, α-synuclein, and TDP-43, and we discuss how these disease-specific properties are maintained in the brain, based on recent experimental insights.

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Section: Experimental Prion-like Amplification and Transmission Of Pa...mentioning

confidence: 99%

Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43

et al. 2022

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“…Production of TDP-43 RRMs for NMR studies was performed as previously described ( 16 ). Production of full-length TDP-43 was performed as previously reported ( 7 ). For more details, see Supplementary materials & methods .…”

Section: Methodsmentioning

confidence: 99%

“…Production of full-length TDP-43 was performed as previously reported (7). For more details, see Supplementary materials & methods.…”

Section: Recombinant Protein Expression and Purificationmentioning

confidence: 99%

“…Importantly, TDP-43 pathology is not an exclusive hallmark of ALS and FTLD, but is also the main pathological feature in limbic-predominant age-related TDP-43 encephalopathy (LATE) (4) and a concomitant pathology in a subset of patients with other neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's disease (5). However, TDP-43 aggregates associated with different clinical subtypes present distinct subcellular localization, namely cytoplasmic, intranuclear or axonal (6,7), as well as morphological and biochemical properties (8)(9)(10), indicating a distinct molecular origin of these diverse pathological species. TDP-43 is a ubiquitously expressed (11) and predominantly nuclear (12) nucleic acidbinding protein (11,13) composed of an N-terminal domain (NTD, amino acids 1-80) involved in self-oligomerization (14,15), two tandem RNA-recognition motifs (RRMs, amino acids 106-259) (13,16) and an unstructured low complexity region (LCR, amino acids 260-414).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TDP-43 oligomerization and RNA binding are codependent but their loss elicits distinct pathologies

Pérez‐Berlanga

Wiersma

Zbinden

et al. 2022

Preprint

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Aggregation of the RNA-binding protein TDP-43 is the main common neuropathological feature of TDP-43 proteinopathies. In physiological conditions, TDP-43 is predominantly nuclear and contained in biomolecular condensates formed via liquid-liquid phase separation (LLPS). However, in disease, TDP-43 is depleted from these compartments and forms cytoplasmic or, sometimes, intranuclear inclusions. How TDP-43 transitions from physiological to pathological states remains poorly understood. Here, we show that self-oligomerization and RNA binding cooperatively govern TDP-43 stability, functionality, LLPS and cellular localization. Importantly, our data reveal that TDP-43 oligomerization is connected to, and conformationally modulated by, RNA binding. Mimicking the impaired proteasomal activity observed in patients, we found that TDP-43 forms nuclear aggregates via LLPS and cytoplasmic aggregates via aggresome formation. The favored aggregation pathway depended on the TDP-43 state –monomeric/oligomeric, RNA-bound/-unbound– and the subcellular environment –nucleus/cytoplasm. Our work unravels the origins of heterogeneous pathological species occurring in TDP-43 proteinopathies.

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Neuronal loss of the nucleus basalis of Meynert in primary progressive aphasia is associated with Alzheimer's disease neuropathological changes

Schaeverbeke

Tomé

Ronisz

et al. 2022

Alzheimer's & Dementia

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Introduction:Imaging studies indicated basal forebrain reduction in primary progressive aphasia (PPA), which might be a candidate marker for cholinergic treatment.Nucleus basalis of Meynert (nbM) neuronal loss has been reported, but a systematic quantitative neuropathological assessment including the three clinical PPA variants is lacking.Methods: Quantitative assessment of neuronal density and pathology was performed on nbM tissue of 47 cases: 15 PPA, constituting the different clinicopathological phenotypes, 14 Alzheimer's disease (AD), and 18 cognitively normals.Results: Group-wise, reduced nbM neuronal density was restricted to AD. At the individual level, semantic variant PPA with underlying AD neuropathological change (ADNC) had lower neuronal densities, while those with frontotemporal lobar degeneration (FTLD) transactive response DNA binding protein 43 kDa (TDP-43) type C pathology were unaffected. Higher Braak stages and increased numbers of nbMrelated pretangles were associated with nbM neuronal loss.Discussion: nbM neuronal loss in PPA is related to ADNC. This study cautions against overinterpreting MRI-based basal forebrain volumes in non-AD PPA as neuronal loss.

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FTLD‐TDP assemblies seed neoaggregates with subtype‐specific features via a prion‐like cascade

Cited by 18 publications

References 74 publications

Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43

Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43

TDP-43 oligomerization and RNA binding are codependent but their loss elicits distinct pathologies

Neuronal loss of the nucleus basalis of Meynert in primary progressive aphasia is associated with Alzheimer's disease neuropathological changes

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