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

Topic: Disease mechanisms in lab and animal studies

Amyloid aggregates of specific proteins constitute important pathological hallmarks in many neurodegenerative diseases, defining neuronal degeneration and disease onset. Recently, increasing numbers of patients show comorbidities and overlaps between multiple neurodegenerative diseases, presenting distinct phenotypes. Such overlaps are often accompanied by colocalizations of more than one amyloid protein, prompting the question of whether direct interactions between different amyloid proteins could generate heterotypic amyloids. To answer this question, we investigated the effect of α-synuclein (αS) on the DNA-binding protein TDP-43 aggregation inspired by their coexistence in pathologies such as Lewy body dementia and limbic predominant age-related TDP-43 encephalopathy. We previously showed αS and prion-like C-terminal domain (PrLD) of TDP-43 synergistically interact to generate toxic heterotypic aggregates. Here, we extend these studies to investigate whether αS induces structurally and functionally distinct polymorphs of PrLD aggregates. Using αS-PrLD heterotypic aggregates generated in two different stoichiometric proportions, we show αS can affect PrLD fibril forms. PrLD fibrils show distinctive residue level signatures determined by solid state NMR, dye-binding capability, proteinase K (PK) stability, and thermal stability toward SDS denaturation. Furthremore, by gold nanoparticle labeling and transmission electron microscopy, we show the presence of both αS and PrLD proteins within the same fibrils, confirming the existence of heterotypic amyloid fibrils. We also observe αS and PrLD colocalize in the cytosol of neuroblastoma cells and show that the heterotypic PrLD fibrils selectively induce synaptic dysfunction in primary neurons. These findings establish the existence of heterotypic amyloid and provide a molecular basis for the observed overlap between synucleinopathies and TDP-43 proteinopathies.

Key findings

• These findings establish the existence of heterotypic amyloid and provide a molecular basis for the observed overlap between synucleinopathies and TDP-43 proteinopathies.

Study details

• Evidence strengthLow

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• DOI: 10.1016/j.jbc.2022.102498
• PubMed: 36116552
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@article{dhakal2022-36116552,
  author  = {Dhakal, Shailendra and Robang, Alicia S and Bhatt, Nemil and Puangmalai, Nicha and Fung, Leiana and Kayed, Rakez and Paravastu, Anant K and Rangachari, Vijayaraghavan},
  title   = {{Distinct neurotoxic TDP-43 fibril polymorphs are generated by heterotypic interactions with α-Synuclein}},
  journal = {The Journal of biological chemistry},
  year    = {2022},
  doi     = {10.1016/j.jbc.2022.102498},
  pmid    = {36116552},
  url     = {https://doi.org/10.1016/j.jbc.2022.102498}
}

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