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

ABSTRACT: Misfolded alpha-synuclein (?Syn) is a major constituent of Lewy bodies and Lewy neurites, which are pathological hallmarks of Parkinson's disease (PD). The contribution of ?Syn to PD is well established, but the detailed mechanism remains obscure. Using a model in which ?Syn aggregation in primary neurons was seeded by exogenously added, preformed ?Syn amyloid fibrils (PFF), we found that a majority of pathogenic ?Syn (indicated by serine 129 phosphorylated ?Syn, ps-?Syn) was membrane-bound and associated with mitochondria. In contrast, only a minuscule amount of physiological ?Syn was mitochondrial bound. In vitro, ?Syn PFF displayed a stronger binding to purified mitochondria than did ?Syn monomer, revealing a preferential mitochondria binding by aggregated ?Syn. This selective mitochondrial ps-?Syn accumulation was confirmed in other neuronal and animal ?Syn 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 ?Syn aggregation (?-synucleinopathies). We also showed that the mitochondrial ps-?Syn 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 ?Syn, pathogenic ?Syn aggregates preferentially bind to mitochondria, indicating mitochondrial dysfunction as the common downstream mechanism for ?-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-?Syn and the mitochondria is a therapeutic target for ?-synucleinopathies.

SUBMITTER: Wang X

PROVIDER: S-EPMC6419482 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Wang Xinhe X Becker Katelyn K Levine Nathan N Zhang Michelle M Lieberman Andrew P AP Moore Darren J DJ Ma Jiyan J

Acta neuropathologica communications 20190314 1

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 ...[more]

PMID: 30871620

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Project description:Parkinson's disease (PD) is characterized neuropathologically by intracellular aggregates of fibrillar α-synuclein, termed Lewy bodies (LBs). Approximately 90% of α-synuclein deposited as LBs is phosphorylated at Ser129 in brains with PD. In contrast, only 4% of total α-synuclein is phosphorylated at Ser129 in brains with normal individuals. It is unclear why extensive phosphorylation occurs in the pathological process of PD. To address this issue, we investigated a mechanism and role of Ser129-phosphorylation in regulating accumulation of α-synuclein. In CHO cells, the levels of Ser129-phosphorylated soluble α-synuclein were maintained constantly to those of total α-synuclein in intracellular and extracellular spaces. In SH-SY5Y cells and rat primary cortical neurons, mitochondrial impairment by rotenone or MPP+ enhanced Ser129-phosphorylation through increased influx of extracellular Ca2+. This elevation was suppressively controlled by targeting Ser129-phosphorylated α-synuclein to the proteasome pathway. Rotenone-induced insoluble α-synuclein was also targeted by Ser129-phosphoryation to the proteasome pathway. Experiments with epoxomicin and chloroquine showed that proteasomal targeting of insoluble Ser129-phosphorylated α-synuclein was enhanced under lysosome inhibition and it reduced accumulation of insoluble total α-synuclein. However, in a rat AAV-mediated α-synuclein overexpression model, there was no difference in the number of total α-synuclein aggregates between A53T mutant and A53T plus S129A double mutant α-synuclein, although Ser129-phosphorylated α-synuclein-positive aggregates were increased in rats expressing A53T α-synuclein. These findings suggest that Ser129-phosphorylation occurs against stress conditions, which increases influx of extracellular Ca2+, and it prevents accumulation of insoluble α-synuclein by evoking proteasomal clearance complementary to lysosomal one. However, Ser129-phosphorylation may provide an ineffective signal for degradation-resistant aggregates, causing extensive phosphorylation in aggregates.

Dataset Information

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

Publications

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

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