Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation

Abstract

Amyloid aggregation of pathological proteins is closely associated with a variety of neurodegenerative diseases, and α-synuclein (α-syn) deposition and Tau tangles are considered hallmarks of Parkinson's disease and Alzheimer's disease, respectively. Intriguingly, α-syn and Tau have been found to co-deposit in the brains of individuals with dementia and parkinsonism, suggesting a potential role of cross-talk between these two proteins in neurodegenerative pathologies. Here we show that monomeric α-syn and the two variants of Tau, Tau23 and K19, synergistically promote amyloid fibrillation, leading to their co-aggregation in vitro. NMR spectroscopy experiments revealed that α-syn uses its highly negatively charged C terminus to directly interact with Tau23 and K19. Deletion of the C terminus effectively abolished its binding to Tau23 and K19 as well as its synergistic effect on promoting their fibrillation. Moreover, an S129D substitution of α-syn, mimicking C-terminal phosphorylation of Ser129 in α-syn, which is commonly observed in the brains of Parkinson's disease patients with elevated α-syn phosphorylation levels, significantly enhanced the activity of α-syn in facilitating Tau23 and K19 aggregation. These results reveal the molecular basis underlying the direct interaction between α-syn and Tau. We proposed that this interplay might contribute to pathological aggregation of α-syn and Tau in neurodegenerative diseases.

Amyloid particles facilitate surface-catalyzed cross-seeding by acting as promiscuous nanoparticles

“…In addition, the importance of primary sequence similarity for the observed cross-seeding between heterologous protein aggregates is not clear (e.g. Lu et al, 2020;Shida et al, 2020). Thus, the current view of cross-seeding through templated elongation alone does not readily explain the synergetic statistical links between amyloid diseases associated with non-homologous proteins (Biessels et al, 2006;Daniele et al, 2018;Sims-Robinson et al, 2010).…”

Looking Beyond the Core: The Role of Flanking Regions in the Aggregation of Amyloidogenic Peptides and Proteins

“…Similarly, CsgA, a bacterial functional amyloid, also accelerates αSyn aggregation, possibly explaining clinical and epidemiological data that show an accumulation of aggregated αSyn first being found in olfactory epithelium or gastrointestinal tract, before spreading to the brain (Sampson et al, 2020). Aggregation assays with a C-terminally truncated variant of αSyn using PRE NMR experiments revealed that the C-terminal region of αSyn interacts with Tau (Dasari et al, 2019;Lu et al, 2020; Table 1). This region is also involved in ion binding, most importantly Ca 2+ , which drives fibril formation probably by changing the conformational dynamics of αSyn to a more extended form (Han et al, 2018).…”

Distinct cryo-EM Structure of α-synuclein Filaments derived by Tau

“…Several lines of evidence indicate that pathological proteins such as -amyloid (A) peptides, tau and α-synuclein synergistically promote their mutual aggregation. 24,[53][54][55][56][57][58][59][60][61] In particular, co-existence of tau and α-synuclein aggregates in synucleinopathy patient's brains suggests that tau may interact with α-synuclein, accelerating the formation of fibrillar α-synuclein aggregates in vivo. In this work, we solved cryo-EM structure of α-synuclein filaments derived by tau and compared the structure to those of previously reported structures of α-synuclein filaments.…”