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.
Highlights
Sporadic Parkinson’s disease (PD) pathology is characterized by substantia nigra pars compacta neuronal loss, systemic dysfunction of the mitochondrial enzyme complex I, and intraneuronal alphasynuclein (a-syn) aggregation (Cardoso et al, 2005)
PD cybrid lines used in this current study show a decrease of 38% in complex I activity and of 28% in ATP levels when compared to the control cybrid lines (Esteves et al, 2008)
We observed that the a-syn oligomer/monomer ratio was higher in the PD cybrid lines (Figures 1B,C), and the PD cybrid lines showed more protein ubiquination levels (Figure 1D)
Summary
Sporadic Parkinson’s disease (PD) pathology is characterized by substantia nigra pars compacta neuronal loss, systemic dysfunction of the mitochondrial enzyme complex I, and intraneuronal alphasynuclein (a-syn) aggregation (Cardoso et al, 2005). While a-syn overexpression and mutation cause familial PD, the mechanisms that mediate this are unclear (Singleton et al, 2003; Hope et al, 2004). This is not surprising, as the normal function of a-syn is itself poorly characterized. Recent data indicate a-syn interacts with microtubules to affect membrane stability and neuronal plasticity (Lee et al, 2006). Conditions that favor incorporation of tubulin into microtubules reduce free/polymerized tubulin ratios, while conditions that retard microtubule formation increase this ratio
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