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Polymorphic ?-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein.

ABSTRACT: The pathological hallmark of synucleinopathies, including Parkinson's disease (PD), is the aggregation of ?-synuclein (?-Syn) protein. Even so, tau protein pathology is abundantly found in these diseases. Both ?-Syn and tau can exist as polymorphic aggregates, a phenomenon that has been widely studied, mostly in their fibrillar assemblies. We have previously discovered that in addition to ?-Syn oligomers, oligomeric tau is also present in the brain tissues of patients with PD and dementia with Lewy bodies (DLB). However, the effect of interaction between polymorphic ?-Syn oligomers and tau has not been scrupulously studied. Here, we have explored the structural and functional diversity of distinct ?-Syn oligomers, prepared by modifying the protein with dopamine (DA) and docosahexaenoic acid (DHA). The two ?-Syn oligomers differed in aggregate size, conformation, sensitivity to proteinase K digestion, tryptic digestion, and toxicity, suggesting them as distinct ?-Syn oligomeric strains. We examined their internalization mechanisms in primary neurons and seeding propensity in inducing ?-Syn aggregation. Using a combined approach of molecular and cellular techniques, we observed that the tau aggregates cross-seeded with the individual ?-Syn oligomeric strains differed in their biochemical and biological properties, suggesting two distinct tau strains. The tau aggregate cross-seeded with the DA-modified ?-Syn oligomeric strain possessed a potent intracellular tau seeding propensity. This study provides a comprehensive analysis of unique strain-specific interaction between oligomeric ?-Syn and tau. Furthermore, this study allows us to speculate that distinct ?-Syn-tau interactions inducing tau aggregation might be an underlying mechanism of neurodegeneration in PD.

SUBMITTER: Sengupta U

PROVIDER: S-EPMC7253398 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Polymorphic α-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein.

Sengupta Urmi U Puangmalai Nicha N Bhatt Nemil N Garcia Stephanie S Zhao Yingxin Y Kayed Rakez R

Molecular neurobiology 20200429 6

The pathological hallmark of synucleinopathies, including Parkinson's disease (PD), is the aggregation of α-synuclein (α-Syn) protein. Even so, tau protein pathology is abundantly found in these diseases. Both α-Syn and tau can exist as polymorphic aggregates, a phenomenon that has been widely studied, mostly in their fibrillar assemblies. We have previously discovered that in addition to α-Syn oligomers, oligomeric tau is also present in the brain tissues of patients with PD and dementia with L ...[more]

PMID: 32350746

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Project description:IntroductionHerein, we expand our previous work on the effects of long chain polyunsaturated fatty acids (LC-PUFA) on the murine hepatic transcriptome using novel statistical and bioinformatic approaches for evaluating microarray data. The analyses focuses on key differences in the transcriptomic response that will influence metabolism following consumption of FUNG (rich in 20:4n6), FISH (rich in 20:5n3, 22:5n3, and 22:6n3) and COMB, the combination of the two.ResultsUsing a variance-stabilized F-statistic, 371 probe sets (out of 13 K probe sets in the Affymetrix Mu11K chip set) were changed by dietary treatment (P < 0.001). Relative to other groups, COMB had unique affects on murine hepatic transcripts involved in cytoskeletal and carbohydrate metabolism; whereas FUNG affected amino acid metabolism via CTNB1 signaling. All three diets affected transcripts linked to apoptosis and cell proliferation, with evidence FISH may have increased apoptosis and decreased cell proliferation via various transcription factors, kinases, and phosphatases. The three diets affected lipid transport, lipoprotein metabolism, and bile acid metabolism through diverse pathways. Relative to other groups, FISH activated cyps that form hydroxylated fatty acids known to affect vascular tone and ion channel activity. FA synthesis and delta 9 desaturation were down regulated by COMB relative to other groups, implying that a FA mixture of 20:4n6, 20:5n3, and 22:6n3 is most effective at down regulating synthesis, via INS1, SREBP, PPAR alpha, and TNF signaling. Heme synthesis and the utilization of heme for hemoglobin production were likely affected by FUNG and FISH. Finally, relative to other groups, FISH increased numerous transcripts linked to combating oxidative such as peroxidases, an aldehyde dehydrogenase, and heat shock proteins, consistent with the major LC-PUFA in FISH (20:5n3, 22:5n3, 22:6n3) being more oxidizable than the major fatty acids in FUNG (20:4n6).ConclusionDistinct transcriptomic, signaling cascades, and predicted affects on murine liver metabolism have been elucidated for 20:4n6-rich dietary oils, 22:6n3-rich oils, and a surprisingly distinct set of genes were affected by the combination of the two. Our results emphasize that the balance of dietary n6 and n3 LC-PUFA provided for infants and in nutritional and neutraceutical applications could have profoundly different affects on metabolism and cell signaling, beyond that previously recognized.

Dataset Information

Polymorphic ?-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein.

Publications

Polymorphic α-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein.

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