Distinct Neurotoxic TDP-43 Fibirl Polymorphs Are Generated By Heterotypic Interactions With α-Synuclein

Authors

Shailendra Dhakal, University of Southern Mississippi
Alicia S. Robang, Georgia Institute of Technology
Nemil Bhatt, University of Texas Medical Branch
Nicha Puangmalai, University of Texas Medical Branch
Leiana Fung, University of Texas Medical Branch
Rakez Kayed, University of Texas Medical Center
Anant K. Paravastu, Georgia Institute of Technology
Vijayaraghavan Rangachari, University of Southern MississippiFollow

Document Type

Article

Publication Date

11-1-2022

Abstract

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.

Comments

Life Sciences; Biochemistry, Biophysics, and Structural Biology; Biochemistry

Publication Title

Journal of Biological Chemistry

Volume

298

Issue

11

Recommended Citation

Dhakal, S., Robang, A. S., Bhatt, N., Puangmalai, N., Fung, L., Kayed, R., Paravastu, A. K., Rangachari, V. (2022). Distinct Neurotoxic TDP-43 Fibirl Polymorphs Are Generated By Heterotypic Interactions With α-Synuclein. Journal of Biological Chemistry, 298(11).
Available at: https://aquila.usm.edu/fac_pubs/20352