Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Abstract

Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.α-synuclein | copper | H50Q mutation | inclusions | protein aggregation

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

“…The capacity of copper to bind to alpha-synuclein at H50 could also be highly relevant for disease pathology in humans. Indeed, the point mutation H50Q which leads to a familial form of PD corresponds to the major copper(II) binding site (Proukakis et al, 2013) and binding of copper(II) to this mutant results in a structurally different species compared to the copper-WT species (Villar-Piqué et al, 2016). The ability of copper to accept or donate electrons implicates it in the production of ROS in PD (Barnham et al, 2004; Barnham and Bush, 2008; Valensin et al, 2016), and it has more recently been shown that in the SN, total tissue copper is decreased (Montes et al, 2014).…”

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

“…Studies indicate that Cu accumulates in specific brain regions of aged subjects (Braidy et al., ; Fu, Jiang, & Zheng, ; Pushkar et al., ; Singh et al., ; Wang, Becker, et al., ; Zatta et al., ). In neurodegenerative diseases, long‐term Cu dyshomeostasis plays a role in oxidative damage, and redox‐active Cu accelerates formation of toxic oligomers associated with some neurodegenerative factors (e.g., Amyloid β, alpha synuclein) (Ahuja, Dev, Tanwar, Selwal, & Tyagi, ; Dell'Acqua et al., ; Greenough et al., ; Kawahara et al., ; Lan, Chen, Chai, & Hu, ; Okita et al., ; Squitti, ; Villar‐Pique et al., ). Thus, some circadian abnormalities observed in aged subjects and those with neurological diseases may involve Cu dyshomeostasis, an idea that warrants further study.…”

Synucleinopathies: Where we are and where we need to go

“…We still do not understand in detail what are the cellular factors that affect aSyn aggregation and cytotoxicity. The current hypothesis suggests that, during the process of aSyn assembly, soluble and cytotoxic oligomers may form and cause cell dysfunction and death (Conway et al, ; Outeiro et al, ; Villar‐Pique et al, ).…”