The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease

Figures & data

Table 1 Summary of the experiments discussed and a categorization of the evidence as direct or indirect

Hypothesis	Experiment(s)	Conclusion	Comments	Proposed experiment(s)
α-synuclein interacts with and influences microtubule stability Direct	In vitro MT assembly assay with and without α-synuclein, sedimentation assay^Citation3	α-synuclein increases the polymerization of MTs	No clarification on whether the turbidity of the solution or insoluble pellet was caused by polymerization of tubulin and not aggregation	Repeating sedimentation assay with the additional step of viewing the final pellet under electron microscopy
	Overexpression of α-synuclein and analysis of MTs via fluorescence microscopy,^Citation3 acetylation,^Citation4 and Golgi fragmentation^Citation5	α-synuclein has a role in the destabilization of microtubules	No MT disruption found in neurons treated with α-synuclein in PFF form: this may be due to the different form of α-synuclein used in this experiment^Citation6	Repeat experiment using PFFs of α-synuclein instead of overexpressing it
α-synuclein acts as an MT dynamase Direct	Turbidity assay with α-synuclein and PD-associated mutants, followed by electron microscopy^Citation7	α-synuclein promotes microtubule polymerization in vitro	Similar experiment showed no effect of α-synuclein on the polymerization of MTs: likely due to procedural differences^Citation8
α-synuclein promotes tau phosphorylation via GSK-3β Indirect	Co-immunoprecipitation of α-synuclein and GSK-3β^Citation21	α-synuclein interacts with GSK-3β	Co-immunoprecipitation does not prove the proteins interact	Use FRET to see whether α-synuclein and GSK-3β interact in vivo
α-synuclein promotes the formation of aggregates Indirect	Overexpression of α-synuclein in mice and immunohistochemical staining for α-synuclein, P-tau and pGSK-3β^Citation19	α-synuclein overexpression results in the formation of aggregates that resemble Lewy bodies	No evidence of tauopathy or synucleinopathy was found in a similar model overexpressing α-synuclein under a different promoter^Citation25
α-synuclein acts synergistically with tau to cause neurodegeneration via tau phosphorylation Indirect	α-synuclein and tau overexpressed in dopaminergic neurons and the phosphorylation state of tau analyzed using antibodies^Citation30	α-synuclein has no effect on tau phosphorylation	Only a few phosphorylation sites were targets of the antibody used to analyze tau phosphorylation	Repeat experiment using antibodies recognizing tau phosphorylated at Ser262 or Ser396, the primary targets of PKA and GSK-3β, respectively

Abbreviations: FRET, fluorescence resonance energy transfer; MTs, microtubules; PD, Parkinson’s disease; PFF, preformed fibril; P-tau, phosphorylated tau.

ZhouRHuangYLiXMolecular interaction of α-synuclein with tubulin influences on the polymerization of microtubule in vitro and structure of microtubule in cellsMol Biol Rep20093773183319219826908

 PubMed Web of Science ®Google Scholar

ProtsIVeberVBreySα-Synuclein oligomers impair neuronal microtubule-kinesin interplayJ Biol Chem201328830217422175423744071

 PubMed Web of Science ®Google Scholar

LeeHKhoshaghidehFLeeSLeeSImpairment of microtubule-dependent trafficking by overexpression of α-synucleinEur J Neurosci200624113153316217156376

 PubMed Web of Science ®Google Scholar

Volpicelli-DaleyLGambleKSchultheissCRiddleDWestALeeVFormation of -synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomesMol Biol Cell201425254010402325298402

 PubMed Web of Science ®Google Scholar

AlimMHossainMArimaKTubulin seeds α-synuclein fibril formationJ Biol Chem200127732112211711698390

 PubMed Web of Science ®Google Scholar

ChenLJinJDavisJOligomeric α-synuclein inhibits tubulin polymerizationBiochem Biophys Res Commun2007356354855317374364

 PubMed Web of Science ®Google Scholar

DukaTDukaVJoyceJSidhuAα-Synuclein contributes to GSK-3β-catalyzed Tau phosphorylation in Parkinson’s disease modelsFASEB J20092392820283019369384

 PubMed Web of Science ®Google Scholar

HaggertyTCredleJRodriguezOHyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson’s diseaseEur J Neurosci20113391598161021453448

 PubMed Web of Science ®Google Scholar

GiassonBInitiation and synergistic fibrillization of tau and alpha-synucleinScience2003300561963664012714745

 PubMed Web of Science ®Google Scholar

RoyBJacksonGInteractions between Tau and α-synuclein augment neurotoxicity in a Drosophila model of Parkinson’s diseaseHum Mol Genet201423113008302324430504

 PubMed Web of Science ®Google Scholar