C-terminal truncation modulates α-Synuclein’s cytotoxicity and aggregation by promoting the interactions with membrane and chaperone

Abstract

Abstractα-Synuclein (α-syn) is the main protein component of Lewy bodies, the major pathological hallmarks of Parkinson’s disease (PD). C-terminally truncated α-syn is found in the brain of PD patients, reduces cell viability and tends to form fibrils. Nevertheless, little is known about the mechanisms underlying the role of C-terminal truncation on the cytotoxicity and aggregation of α-syn. Here, we use nuclear magnetic resonance spectroscopy to show that the truncation alters α-syn conformation, resulting in an attractive interaction of the N-terminus with membranes and molecular chaperone, protein disulfide isomerase (PDI). The truncated protein is more toxic to mitochondria than full-length protein and diminishes the effect of PDI on α-syn fibrillation. Our findings reveal a modulatory role for the C-terminus in the cytotoxicity and aggregation of α-syn by interfering with the N-terminus binding to membranes and chaperone, and provide a molecular basis for the pathological role of C-terminal truncation in PD pathogenesis.

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

“…Reduced activity of protein degradation systems, such as proteasomes, autophagic systems and lysosomes occur in patients with synucleinopathies. Therefore, the activation of autophagy gives hope for future therapeutic applications [ 36 , 79 , 82 , 83 ]. There are approaches that are not aimed at α-synuclein in a straight line but affect it indirectly.…”

“…Autophagy is critically related to the anomalous accumulation of α-synuclein, and defects in lysosome-related transmembrane ATP transport enzyme ATP13A2 (also known as PARK9) impair lysosomal function and inhibit the toxicity of α-synuclein. Therefore, this enzyme may be considered a possible target in synucleinopathies [ 36 , 62 ]. Other autophagy activation methods also give hope for future therapeutic applications [ 82 ].…”

“…Proteolytic truncation of α-synuclein C-terminus also accelerates its aggregation and increases toxicity. The C-terminus determines α-synuclein cytotoxicity and aggregation by regulating binding to membranes and chaperones [ 36 ].…”

Liquid-Liquid Phase Separation Promotes Protein Aggregation and Its Implications in Ferroptosis in Parkinson’s Disease Dementia

“…Among them, polyanionic factors such as heparin are particularly effective, but at the same time, specific but unknown phosphorylation modes are required [ 64 , 89 ]. LLPS without heparin and heparin-induced fibrosis depend on the temperature and ionic strength of K18 solution similarly, while heparin-induced K18 fibrosis can form amyloid more efficiently at alkaline pH [ 73 , 90 ]. Recent work also showed that following incubation with PEG, the prolonged LLPS of tau leads to the adoption of known pathogenic conformations of tau, such as oligomers and N-terminal exposure.…”

Intrinsic Disorder in α-Synuclein Regulates the Exocytotic Fusion Pore Transition

“…Also, long-range interactions between the N- and C-terminal regions in monomeric α-synuclein have been shown to stabilize its native compact conformations, both experimentally and computationally . As a consequence, diverse forms of truncated α-synucleins have been studied in relation to Parkinson’s disease. − Remarkably, it has been recently proposed that the C-terminal region of α-synuclein balances the interactions between the N-terminal and the membrane, while its truncation facilitates membrane binding . Such results have implications in the cytotoxicity and aggregation of α-synuclein, specifically for the relation of C-terminal truncation to the pathogenesis of Parkinson’s disease …”