Mechanistic basis for receptor-mediated pathological α-synuclein fibril cell-to-cell transmission in Parkinson's disease

Abstract

The spread of pathological α-synuclein (α-syn) is a crucial event in the progression of Parkinson’s disease (PD). Cell surface receptors such as lymphocyte activation gene 3 (LAG3) and amyloid precursor-like protein 1 (APLP1) can preferentially bind α-syn in the amyloid over monomeric state to initiate cell-to-cell transmission. However, the molecular mechanism underlying this selective binding is unknown. Here, we perform an array of biophysical experiments and reveal that LAG3 D1 and APLP1 E1 domains commonly use an alkaline surface to bind the acidic C terminus, especially residues 118 to 140, of α-syn. The formation of amyloid fibrils not only can disrupt the intramolecular interactions between the C terminus and the amyloid-forming core of α-syn but can also condense the C terminus on fibril surface, which remarkably increase the binding affinity of α-syn to the receptors. Based on this mechanism, we find that phosphorylation at serine 129 (pS129), a hallmark modification of pathological α-syn, can further enhance the interaction between α-syn fibrils and the receptors. This finding is further confirmed by the higher efficiency of pS129 fibrils in cellular internalization, seeding, and inducing PD-like α-syn pathology in transgenic mice. Our work illuminates the mechanistic understanding on the spread of pathological α-syn and provides structural information for therapeutic targeting on the interaction of α-syn fibrils and receptors as a potential treatment for PD.

Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies

“…Importantly, the reduction was non total, and in the same study Mao and coworkers revealed that the Ab precursor-like protein 1 (APLP1) also act as a receptor leading to the entry of αSyn fibrils [ 190 ]. In very recent work, Zhang and coworkers investigated in more detail the molecular mechanism underlying the selective binding of fibrillar αSyn to neuronal cells through Lag-3 and APLP1 receptors, revealing that the acidic C-terminus of αSyn, particularly exposed on the surface of fibrillar conformers, is the key domain binding to a positively charged surface on the analysed receptors [ 206 ]. Importantly, S129 phosphorylation of αSyn, a typical modification of pathological αSyn abundant in Lewy bodies and neurites, determines a significant increase in the binding of αSyn fibrils to the receptors, thus promoting their spreading, finally culminating in neurodegeneration [ 206 ].…”

Alpha-Synuclein Aggregation Pathway in Parkinson’s Disease: Current Status and Novel Therapeutic Approaches

“…Related to that, it is not surprising that α-Syn adopts a monomeric, random coil conformation in an aqueous medium, while its interaction with lipid membranes drives the transition of the protein part (N-terminus and NAC region) into defined α-helical structures ( Figure 1 ) [ 60 , 62 ]. The dynamic C-terminal part is involved in interactions with ligands (ions, polyanions, and polycations), protein partners, and membrane binding [ 24 , 68 ]. Within the C-terminal domain, residues 120–130 were shown to interact with residues 105–115, while positively charged N-terminal residues can interact with negatively charged C-terminal residues, forming a closed α-Syn conformational state [ 69 ].…”

“…Cell-to-cell transfer mediated by receptors, or the so-called ‘prion-like’ hypothesis, suggests that α-Syn oligomers can migrate between neurons [ 6 ]. Moreover, the acidic α-Syn C-terminus interacts with alkaline patches on the cell surface receptors, such as lymphocyte activation gene 3 (LAG3) and amyloid precursor-like protein 1 [ 68 ]. Amyloid fibril formation dramatically enhances (>200 times) binding to receptors due to the more accessible C-terminus that is shielded in the monomer.…”

Characterization of a Novel Monoclonal Antibody for Serine-129 Phosphorylated α-Synuclein: A Potential Application for Clinical and Basic Research

“…Phosphorylation at serine-129 was reported to induce the formation of distinct α-syn strains (14), and phosphorylated exogenous α-syn fibrils could exacerbate pathology and induce neuronal dysfunction in mice (15). A recent report also concluded that p-α-syn enhanced the interaction between αsyn fibrils and its receptors, which meant that p-α-syn could facilitate the spread of α-syn pathologies (16). Overall, the role of p-α-syn is relatively complicated, and further studies Abbreviations: α-syn, α-synuclein; AP, alkaline phosphatase; β-syn, β-synuclein; BCA, bicinchoninic acid; C, C-terminal domain of α-synuclein (residues 96-140); CBS, Coomassie Brilliant Blue staining; ELISA, enzyme-linked immunosorbent assay; h-α-syn, human α-synuclein; m-α-syn, mouse α-synuclein; MS, mass spectrometry; N, N-terminal domain of α-synuclein (N-α-syn, residues 1-60); N, N-terminal domain of α-synuclein; NAC, non-amyloid component, the central domain of α-synuclein (residues 61-95); p, phospho-group; p-α-syn, serine-129site phosphorylated α-synuclein; PD, Parkinson's disease; PFF, preformed fibrils; PLK3, Polo-Like-Kinase 3; pNPP, p-nitrophenyl phosphate; KO, α-syn knockout mice; R, rabbit; SD, standard deviation; SEM, standard error of the mean; TEM, transmission electron microscopy; Tg, Thy1-SNCA transgenic mice; ThT, thioflavin T; Wt, wild-type brood mice.…”

“…Phosphorylation at serine-129 was reported to induce the formation of distinct α-syn strains ( 14 ), and phosphorylated exogenous α-syn fibrils could exacerbate pathology and induce neuronal dysfunction in mice ( 15 ). A recent report also concluded that p-α-syn enhanced the interaction between α-syn fibrils and its receptors, which meant that p-α-syn could facilitate the spread of α-syn pathologies ( 16 ). Overall, the role of p-α-syn is relatively complicated, and further studies are still needed to reveal its exact mechanism involved in PD pathologies.…”