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Microtubule depolymerization potentiates alpha-synuclein oligomerization.

Esteves AR, Arduíno DM, Swerdlow RH, Oliveira CR, Cardoso SM - Front Aging Neurosci (2010)

Bottom Line: Compared to a control cybrid cell line, the PD line showed reduced ATP levels, an increased free/polymerized tubulin ratio, and alpha-synuclein oligomer accumulation.Taxol (which stabilizes microtubules) normalized the PD tubulin ratio and reduced alpha-synuclein oligomerization.In our model, mitochondrial dysfunction triggers an increased free tubulin, which destabilizes the microtubular network and promotes alpha-synuclein oligomerization.

View Article: PubMed Central - PubMed

Affiliation: Centro de Neurociências e Biologia Celular, Universidade de Coimbra Portugal.

ABSTRACT
Parkinson's disease (PD) is associated with perturbed mitochondria function and alpha-synuclein fibrillization. We evaluated potential mechanistic links between mitochondrial dysfunction and alpha-synuclein aggregation. We studied a PD cytoplasmic hybrid (cybrid) cell line in which platelet mitochondria from a PD subject were transferred to NT2 neuronal cells previously depleted of endogenous mitochondrial DNA. Compared to a control cybrid cell line, the PD line showed reduced ATP levels, an increased free/polymerized tubulin ratio, and alpha-synuclein oligomer accumulation. Taxol (which stabilizes microtubules) normalized the PD tubulin ratio and reduced alpha-synuclein oligomerization. A nexus exists between mitochondrial function, cytoskeleton homeostasis, and alpha-synuclein oligomerization. In our model, mitochondrial dysfunction triggers an increased free tubulin, which destabilizes the microtubular network and promotes alpha-synuclein oligomerization.

No MeSH data available.


Related in: MedlinePlus

Effects of taxol on tubulin and alpha synuclein. (A) SDS-PAGE showing the effect of 5 nM taxol on free/polymerized tubulin ratios. (B) Densitometry analysis indicated after correcting for GADPH content, 5 nM taxol reduced the free/polymerized tubulin ratio in the PD but not the CT cybrid cells. (C) PAGE showing the effect of 5 nM taxol on alpha-synuclein oligomer levels. (D) Densitometry analysis indicated 5 nM taxol reduced alpha synuclein oligomer levels in the PD cybrid cells. **P < 0.01, significantly different when compared to the untreated CT cybrid cells. #P < 0.05 and ##P < 0.01, significantly different as compared to the untreated PD cybrid line.
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Figure 3: Effects of taxol on tubulin and alpha synuclein. (A) SDS-PAGE showing the effect of 5 nM taxol on free/polymerized tubulin ratios. (B) Densitometry analysis indicated after correcting for GADPH content, 5 nM taxol reduced the free/polymerized tubulin ratio in the PD but not the CT cybrid cells. (C) PAGE showing the effect of 5 nM taxol on alpha-synuclein oligomer levels. (D) Densitometry analysis indicated 5 nM taxol reduced alpha synuclein oligomer levels in the PD cybrid cells. **P < 0.01, significantly different when compared to the untreated CT cybrid cells. #P < 0.05 and ##P < 0.01, significantly different as compared to the untreated PD cybrid line.

Mentions: Taxol stabilizes MT assemblies and reduces free tubulin/polymerized tubulin ratios (Cragg and Newman, 2005). Before testing its effects in our cybrid model (which consists of undifferentiated, rapidly dividing cells) we determined 5 nM taxol did not compromise cell viability (data not shown). 5 nM taxol reduced the free tubulin/polymerized tubulin ratio in the PD cybrid lines but not in the control cybrid lines (Figures 3A,B). Taxol lowered a-syn oligomerization in PD cybrid cells but did not altered CT cybrid cells a-syn levels (Figures 3C,D). These results support the idea that MT depolymerization may potentiate the formation of oligomeric a-syn.


Microtubule depolymerization potentiates alpha-synuclein oligomerization.

Esteves AR, Arduíno DM, Swerdlow RH, Oliveira CR, Cardoso SM - Front Aging Neurosci (2010)

Effects of taxol on tubulin and alpha synuclein. (A) SDS-PAGE showing the effect of 5 nM taxol on free/polymerized tubulin ratios. (B) Densitometry analysis indicated after correcting for GADPH content, 5 nM taxol reduced the free/polymerized tubulin ratio in the PD but not the CT cybrid cells. (C) PAGE showing the effect of 5 nM taxol on alpha-synuclein oligomer levels. (D) Densitometry analysis indicated 5 nM taxol reduced alpha synuclein oligomer levels in the PD cybrid cells. **P < 0.01, significantly different when compared to the untreated CT cybrid cells. #P < 0.05 and ##P < 0.01, significantly different as compared to the untreated PD cybrid line.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874407&req=5

Figure 3: Effects of taxol on tubulin and alpha synuclein. (A) SDS-PAGE showing the effect of 5 nM taxol on free/polymerized tubulin ratios. (B) Densitometry analysis indicated after correcting for GADPH content, 5 nM taxol reduced the free/polymerized tubulin ratio in the PD but not the CT cybrid cells. (C) PAGE showing the effect of 5 nM taxol on alpha-synuclein oligomer levels. (D) Densitometry analysis indicated 5 nM taxol reduced alpha synuclein oligomer levels in the PD cybrid cells. **P < 0.01, significantly different when compared to the untreated CT cybrid cells. #P < 0.05 and ##P < 0.01, significantly different as compared to the untreated PD cybrid line.
Mentions: Taxol stabilizes MT assemblies and reduces free tubulin/polymerized tubulin ratios (Cragg and Newman, 2005). Before testing its effects in our cybrid model (which consists of undifferentiated, rapidly dividing cells) we determined 5 nM taxol did not compromise cell viability (data not shown). 5 nM taxol reduced the free tubulin/polymerized tubulin ratio in the PD cybrid lines but not in the control cybrid lines (Figures 3A,B). Taxol lowered a-syn oligomerization in PD cybrid cells but did not altered CT cybrid cells a-syn levels (Figures 3C,D). These results support the idea that MT depolymerization may potentiate the formation of oligomeric a-syn.

Bottom Line: Compared to a control cybrid cell line, the PD line showed reduced ATP levels, an increased free/polymerized tubulin ratio, and alpha-synuclein oligomer accumulation.Taxol (which stabilizes microtubules) normalized the PD tubulin ratio and reduced alpha-synuclein oligomerization.In our model, mitochondrial dysfunction triggers an increased free tubulin, which destabilizes the microtubular network and promotes alpha-synuclein oligomerization.

View Article: PubMed Central - PubMed

Affiliation: Centro de Neurociências e Biologia Celular, Universidade de Coimbra Portugal.

ABSTRACT
Parkinson's disease (PD) is associated with perturbed mitochondria function and alpha-synuclein fibrillization. We evaluated potential mechanistic links between mitochondrial dysfunction and alpha-synuclein aggregation. We studied a PD cytoplasmic hybrid (cybrid) cell line in which platelet mitochondria from a PD subject were transferred to NT2 neuronal cells previously depleted of endogenous mitochondrial DNA. Compared to a control cybrid cell line, the PD line showed reduced ATP levels, an increased free/polymerized tubulin ratio, and alpha-synuclein oligomer accumulation. Taxol (which stabilizes microtubules) normalized the PD tubulin ratio and reduced alpha-synuclein oligomerization. A nexus exists between mitochondrial function, cytoskeleton homeostasis, and alpha-synuclein oligomerization. In our model, mitochondrial dysfunction triggers an increased free tubulin, which destabilizes the microtubular network and promotes alpha-synuclein oligomerization.

No MeSH data available.


Related in: MedlinePlus