Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration

Abstract

Misfolded alpha-synuclein (αSyn) is a major constituent of Lewy bodies and Lewy neurites, which are pathological hallmarks of Parkinson’s disease (PD). The contribution of αSyn to PD is well established, but the detailed mechanism remains obscure. Using a model in which αSyn aggregation in primary neurons was seeded by exogenously added, preformed αSyn amyloid fibrils (PFF), we found that a majority of pathogenic αSyn (indicated by serine 129 phosphorylated αSyn, ps-αSyn) was membrane-bound and associated with mitochondria. In contrast, only a minuscule amount of physiological αSyn was mitochondrial bound. In vitro, αSyn PFF displayed a stronger binding to purified mitochondria than did αSyn monomer, revealing a preferential mitochondria binding by aggregated αSyn. This selective mitochondrial ps-αSyn accumulation was confirmed in other neuronal and animal αSyn aggregation models that do not require exogenously added PFF and, more importantly, in postmortem brain tissues of patients suffering from PD and other neurodegenerative diseases with αSyn aggregation (α-synucleinopathies). We also showed that the mitochondrial ps-αSyn accumulation was accompanied by defects in cellular respiration in primary neurons, suggesting a link to mitochondrial dysfunction. Together, our results show that, contrary to physiological αSyn, pathogenic αSyn aggregates preferentially bind to mitochondria, indicating mitochondrial dysfunction as the common downstream mechanism for α-synucleinopathies. Our findings suggest a plausible model explaining the formation and the peculiar morphology of Lewy body and reveal that disrupting the interaction between ps-αSyn and the mitochondria is a therapeutic target for α-synucleinopathies.Electronic supplementary materialThe online version of this article (10.1186/s40478-019-0696-4) contains supplementary material, which is available to authorized users.

Insulin Resistance Promotes Parkinson’s Disease through Aberrant Expression of α-Synuclein, Mitochondrial Dysfunction, and Deregulation of the Polo-Like Kinase 2 Signaling

“…Adding to the numerous roles ascribed to SNCA, including in the pathogenesis of PD, there are accruing suggestions of its role in the regulation of neuronal mitochondrial homeostasis [49][50][51]. Consistent with the findings of the present study, we posit a novel link between mitochondrial dysfunction and aberration in SNCA expression and/or activity.…”

The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration

“…Decreased respiration has already been shown in previous studies in the neuronal seeding model. However, respiration was assessed only between 8/9 and 14 d after PFFs treatment using mouse cortical neurons (73) or rat midbrain neurons (74), respectively. Importantly, in these previous studies high PFF concentrations (140 nM or 350 nM) were used, which in our hands induce cell death events faster.…”

Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

“…Impaired electron transport chain function due to aggregated forms of α-synuclein has been repeatedly reported in cellular models (Chinta et al, 2010; Reeve et al, 2015) (Tapias et al, 2017; Kim et al, 2018; Wang et al, 2019), especially at late stages of aggregation formation (Mahul-Mellier et al, 2019), while functional assessment of mitochondria in in-vivo models of pathology seeding remains lacking. Therefore, we aimed to study mitochondrial respiration directly on fresh brain tissue from regions affected by α-synuclein pathology using ex-vivo respirometry, the gold standard to assess mitochondrial function.…”