Distinguishing post‐translational modifications in dominantly inherited frontotemporal dementias: FTLD‐TDP Type A (<i>GRN</i>) vs Type B (<i>C9orf72</i>)

Cracco, Laura; Doud, Emma H.; Hallinan, Grace I; Garringer, Holly J.; Jacobsen, Max; Richardson, Rose; Buratti, Emanuele; Vidal, Rubén; Ghetti, Bernardino; Newell, Kathy L.

doi:10.1111/nan.12836

Cited by 7 publications

(5 citation statements)

References 68 publications

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“…This includes S347 and S350, which are buried in the double-spiral fold but solvent exposed in the chevron fold. Recently, phosphorylation of S350 was identified in assembled TDP-43 from an individual with type A FTLD-TDP but not that from individuals with ALS and type B FTLD-TDP 18 . It remains to be determined whether phosphorylation occurs before or after filament formation.…”

Section: Comparison Of Tdp-43 Filament Foldsmentioning

confidence: 97%

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

Arseni

Chen

Peak‐Chew

et al. 2023

Nature

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The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases of amyotrophic lateral sclerosis (ALS) and around half of cases of frontotemporal lobar degeneration (FTLD)1,2. A causal role for TDP-43 assembly in neurodegeneration is evidenced by dominantly inherited missense mutations in TARDBP, the gene encoding TDP-43, that promote assembly and give rise to ALS and FTLD3–7. At least four types (A–D) of FTLD with TDP-43 pathology (FTLD-TDP) are defined by distinct brain distributions of assembled TDP-43 and are associated with different clinical presentations of frontotemporal dementia8. We previously showed, using cryo-electron microscopy, that TDP-43 assembles into amyloid filaments in ALS and type B FTLD-TDP9. However, the structures of assembled TDP-43 in FTLD without ALS remained unknown. Here we report the cryo-electron microscopy structures of assembled TDP-43 from the brains of three individuals with the most common type of FTLD-TDP, type A. TDP-43 formed amyloid filaments with a new fold that was the same across individuals, indicating that this fold may characterize type A FTLD-TDP. The fold resembles a chevron badge and is unlike the double-spiral-shaped fold of ALS and type B FTLD-TDP, establishing that distinct filament folds of TDP-43 characterize different neurodegenerative conditions. The structures, in combination with mass spectrometry, led to the identification of two new post-translational modifications of assembled TDP-43, citrullination and monomethylation of R293, and indicate that they may facilitate filament formation and observed structural variation in individual filaments. The structures of TDP-43 filaments from type A FTLD-TDP will guide mechanistic studies of TDP-43 assembly, as well as the development of diagnostic and therapeutic compounds for TDP-43 proteinopathies.

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Section: Comparison Of Tdp-43 Filament Foldsmentioning

confidence: 97%

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

Arseni

Chen

Peak‐Chew

et al. 2023

Nature

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“…The autopsy series included frontal cortex tissues from 16 subjects: 10 diagnosed with FTLD‐TDP (5 carriers of GRN variants and 5 with C9orf72 repeat expansions) and 6 patients with non–TDP‐43 related diagnosis (3 with multiple system tauopathy with dementia [MSTD] and 3 control subjects lacking TDP‐43 pathology; 1 see Table S1 in supporting information for details). Several of these cases have been extensively characterized before 17–19 . Brain specimens from all the aforementioned cases were used to optimize the SAA.…”

Section: Methodsmentioning

confidence: 99%

“…Several of these cases have been extensively characterized before. 17 , 18 , 19 Brain specimens from all the aforementioned cases were used to optimize the SAA.…”

Section: Methodsmentioning

confidence: 99%

Detection of TDP‐43 seeding activity in the olfactory mucosa from patients with frontotemporal dementia

Fontana,

Bongianni,

Benussi

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONWe assessed TAR DNA‐binding protein 43 (TDP‐43) seeding activity and aggregates detection in olfactory mucosa of patients with frontotemporal lobar degeneration with TDP‐43‐immunoreactive pathology (FTLD‐TDP) by TDP‐43 seeding amplification assay (TDP43‐SAA) and immunocytochemical analysis.METHODSThe TDP43‐SAA was optimized using frontal cortex samples from 16 post mortem cases with FTLD‐TDP, FTLD with tau inclusions, and controls. Subsequently, olfactory mucosa samples were collected from 17 patients with FTLD‐TDP, 15 healthy controls, and three patients carrying MAPT variants.RESULTSTDP43‐SAA discriminated with 100% accuracy post mortem cases presenting or lacking TDP‐43 neuropathology. TDP‐43 seeding activity was detectable in the olfactory mucosa, and 82.4% of patients with FTLD‐TDP tested positive, whereas 86.7% of controls tested negative (P < 0.001). Two out of three patients with MAPT mutations tested negative. In TDP43‐SAA positive samples, cytoplasmatic deposits of phosphorylated TDP‐43 in the olfactory neural cells were detected.DISCUSSIONTDP‐43 aggregates can be detectable in olfactory mucosa, suggesting that TDP43‐SAA might be useful for identifying and monitoring FTLD‐TDP in living patients.

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“…Finally, a possible explanation for coaggregation, along with different aggregation profiles in NDDs, could also be related to posttranslational modifications (PTMs) of proteins involved in neurodegeneration [53]. PTM homeostasis is disrupted in NDDs, and there is growing evidence that PTMs may be related to the phenotypic diversity of NDDs [53][54][55][56]. For instance, some TDP-43 PTMs are specific to FTLD-TDP type A (associated with GRN mutations) and some are specific to type B (associated with C9orf72 mutations) [55], phosphorylated Tyr526 FUS is present in the FTLD-FUS pathology [54,56], and the acetylation of K280/K281 in tau increases aggregation in AD.…”

Section: Overlapping Proteinopathiesmentioning

confidence: 99%

“…PTM homeostasis is disrupted in NDDs, and there is growing evidence that PTMs may be related to the phenotypic diversity of NDDs [53][54][55][56]. For instance, some TDP-43 PTMs are specific to FTLD-TDP type A (associated with GRN mutations) and some are specific to type B (associated with C9orf72 mutations) [55], phosphorylated Tyr526 FUS is present in the FTLD-FUS pathology [54,56], and the acetylation of K280/K281 in tau increases aggregation in AD. However, further research is needed to fully understand the role of PTMs in protein aggregation comorbidities.…”

Section: Overlapping Proteinopathiesmentioning

confidence: 99%

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders

De Marchi,

Munitic,

Vidatic

et al. 2023

Biomedicines

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Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer’s (AD) disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann–Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.

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Distinguishing post‐translational modifications in dominantly inherited frontotemporal dementias: FTLD‐TDP Type A (GRN) vs Type B (C9orf72)

Cited by 7 publications

References 68 publications

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

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

Detection of TDP‐43 seeding activity in the olfactory mucosa from patients with frontotemporal dementia

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders

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