Distinct neurotoxic TDP-43 fibril polymorphs are generated by heterotypic interactions with α-Synuclein

Dhakal, Shailendra; Robang, Alicia S.; Bhatt, Nemil; Puangmalai, Nicha; Fung, Leiana; Kayed, Rakez; Paravastu, Anant K.; Rangachari, Vijayaraghavan

doi:10.1016/j.jbc.2022.102498

Cited by 12 publications

(18 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The synergistic interactions between α-synuclein and TDP-43 have also been reported in terms of their fibril assembly and cellular cytotoxicity. Notably, although either soluble or pathological α-synuclein promoted the fibrillization and liquid droplets formation of the C-terminal domain of TDP-43 (TDP-43 PrLD), TDP-43 PrLD fibrils failed to templating α-synuclein in in vitro experiments, indicating a non-bidirectional modulation on the pathogenesis between α-synuclein and TDP43, similar to the interaction between α-synuclein and tau as summarized above ( Dhakal et al, 2021 , 2022 ). However, in vivo evidence supports a mutual synergistic interaction between them.…”

Section: The Synergistic Interactions Between Synuclein Pathology And...mentioning

confidence: 92%

“…The pathologies presented in the brains of the patients with neurodegenerative diseases frequently include more than one hallmark proteins ( Gorell et al, 1994 ; Lomen-Hoerth et al, 2002 ; Bahia et al, 2013 ; Irwin et al, 2013 ; Robinson et al, 2021 ). Moreover, studies have reported the protein–protein interactions among these neuropathological hallmark proteins, suggesting certain mechanisms underlying the pathogenesis of concomitant protein pathogenesis ( Giasson et al, 2003 ; Badiola et al, 2011 ; Nonaka et al, 2018 ; Bassil et al, 2020 , 2021 ; Dhakal et al, 2022 ). Here, we summarize recent data about this comorbidity issue in Parkinson’s disease, from clinical overlapped symptoms, to molecular synergistic interactions, hoping to inspire the efforts to understand the mechanisms and biological implications of the comorbidities in PD and other related neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Concomitant protein pathogenesis in Parkinson’s disease and perspective mechanisms

Han¹,

He²

2023

Front. Aging Neurosci.

View full text Add to dashboard Cite

Comorbidity is a common phenotype in Parkinson’s disease (PD). Patients with PD not only have motor deficit symptoms, but also have heterogeneous non-motor symptoms, including cognitive impairment and emotional changes, which are the featured symptoms observed in patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD) and cerebrovascular disease. Moreover, autopsy studies have also confirmed the concomitant protein pathogenesis, such as the co-existences of α-synuclein, amyloid-β and tau pathologies in PD and AD patients’ brains. Here, we briefly summarize the recent reports regarding the comorbidity issues in PD from both clinical observations and neuropathological evidences. Furthermore, we provide some discussion about the perspective potential mechanisms underlying such comorbidity phenomenon, with a focus on PD and related neurodegenerative diseases.

show abstract

Section: The Synergistic Interactions Between Synuclein Pathology And...mentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Concomitant protein pathogenesis in Parkinson’s disease and perspective mechanisms

Han¹,

He²

2023

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…However, there are increasing number of reports that evidence the existence of heterotypic interactions in amyloid aggregation and their potential impact on aggregation kinetics and toxicity. For example, structures of mixed fibrils of synuclein and the TAR DNA-binding protein (TDP-43) 32 , and a heterotypic amyloid signaling complex 29 have recently been identified by NMR. It has been shown that interactions with homologous non-Aβ peptides and different isoforms can alter aggregation kinetics and fibril morphology of Aβ 22, 28 .…”

Section: Resultsmentioning

confidence: 99%

Heterotypic Seeding Generates Mixed Amyloid Polymorphs

Banerjee,

Baghel,

Edmonds

et al. 2024

Preprint

View full text Add to dashboard Cite

Aggregation of the amyloid beta (Abeta) peptide into fibrils represents one of the major biochemical pathways underlying the development of Alzheimers disease (AD). Extensive studies have been carried out to understand the role of fibrillar seeds on the overall kinetics of amyloid aggregation. However, the precise effect of seeds that are structurally or sequentially different from Abeta; on the structure of the resulting amyloid aggregates is yet to be fully understood. In this work, we use nanoscale infrared spectroscopy to probe the spectral facets of individual aggregates formed by aggregating Abeta42 with antiparallel fibrillar seeds of Abeta(16-22) and E22Q Abeta(1-40) Dutch mutant and demonstrate that Abeta; can form heterotypic or mixed polymorphs that deviate significantly from its expected parallel cross β structure. We further show that formation of heterotypic aggregates is not limited to coaggregation of Abeta; and its isomers, and that the former can form heterotypic fibrils with alpha synuclein and brain protein lysates. These findings highlight the complexity of Abeta; aggregation in AD and underscore the need to explore how Abeta; interacts with other brain components, which is crucial for developing better therapeutic strategies for AD.

show abstract

“…Thus, the direct Aβ-αS interactions extend further with tau through the shared release, trafficking and uptake mechanisms ( Twohig and Nielsen, 2019 ; Visanji et al, 2019 ), that allow intra- and inter-cellular propagation of pathological seeds of Aβ, αS and tau ( Frost et al, 2009 ; Irwin et al, 2013 ; Kayed et al, 2020 ), initiating an autocatalytic cycle of aggregation ( Vasconcelos et al, 2016 ) and spreading pathology ( Lloyd et al, 2021 ). The protein-protein interaction network centered on Aβ-αS can also extend with a non-amyloidogenic protein, such as DNA-binding protein TDP-43, known to bind to αS ( Dhakal et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Oligomerization by co-assembly of β-amyloid and α-synuclein

Kim

2023

Front. Mol. Biosci.

View full text Add to dashboard Cite

Aberrant self-assembly of an intrinsically disordered protein is a pathological hallmark of protein misfolding diseases, such as Alzheimer’s and Parkinson’s diseases (AD and PD, respectively). In AD, the 40–42 amino acid-long extracellular peptide, β-amyloid (Aβ), self-assembles into oligomers, which eventually aggregate into fibrils. A similar self-association of the 140 amino acid-long intracellular protein, α-synuclein (αS), is responsible for the onset of PD pathology. While Aβ and αS are primarily extracellular and intracellular polypeptides, respectively, there is evidence of their colocalization and pathological overlaps of AD and PD. This evidence has raised the likelihood of synergistic, toxic protein-protein interactions between Aβ and αS. This mini review summarizes the findings of studies on Aβ-αS interactions related to enhanced oligomerization via co-assembly, aiming to provide a better understanding of the complex biology behind AD and PD and common pathological mechanisms among the major neurodegenerative diseases.

show abstract

Distinct neurotoxic TDP-43 fibril polymorphs are generated by heterotypic interactions with α-Synuclein

Cited by 12 publications

References 94 publications

Concomitant protein pathogenesis in Parkinson’s disease and perspective mechanisms

Concomitant protein pathogenesis in Parkinson’s disease and perspective mechanisms

Heterotypic Seeding Generates Mixed Amyloid Polymorphs

Oligomerization by co-assembly of β-amyloid and α-synuclein

Contact Info

Product

Resources

About