Abstract
Parkinson’s disease (PD) is neuropathologically characterized by the loss of dopaminergic neurons and the deposition of aggregated alpha synuclein (aSyn). Mounting evidence suggests that neuritic degeneration precedes neuronal loss in PD. A possible underlying mechanism could be the interference of aSyn with microtubule organization in the neuritic development, as implied by several studies using cell-free model systems. In this study, we investigate the impact of aSyn on microtubule organization in aSyn overexpressing H4 neuroglioma cells and midbrain dopaminergic neuronal cells (mDANs) generated from PD patient-derived human induced pluripotent stem cells (hiPSCs) carrying an aSyn gene duplication (SNCADupl). An unbiased mass spectrometric analysis reveals a preferential binding of aggregated aSyn conformers to a number of microtubule elements. We confirm the interaction of aSyn with beta tubulin III in H4 and hiPSC-derived mDAN cell model systems, and demonstrate a remarkable redistribution of tubulin isoforms from the soluble to insoluble fraction, accompanied by a significantly increased insoluble aSyn level. Concordantly, SNCADupl mDANs show impaired neuritic phenotypes characterized by perturbations in neurite initiation and outgrowth. In summary, our findings suggest a mechanistic pathway, through which aSyn aggregation interferes with microtubule organization and induces neurite impairments.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder worldwide, clinically hallmarked by motor symptoms, such as bradykinesia, rigidity, and resting tremor
We investigate the impact of alpha synuclein (aSyn) on microtubule organization and neuritic integrity using aSyn overexpressing H4 cells and human induced pluripotent stem cells (hiPSCs)-derived neuronal cells generated from a PD patient carrying a heterozygous duplication of the SNCA locus
Our data suggest a mechanistic link between aSyn overexpression, aSyn aggregation, altered aSyn-tubulin interaction and microtubule organization, as well as impaired neuritic integrity in patient-derived neurons
Summary
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder worldwide, clinically hallmarked by motor symptoms, such as bradykinesia, rigidity, and resting tremor. Koch et al reported affected neurite morphology and axonal transport in rat primary midbrain neurons overexpressing wild type and mutant aSyn induced by viral transduction [8] In agreement with these findings in rodent-derived neurons, we observed a severely impaired axonal transport in human cortical projection neurons (CPNs), differentiated from human induced pluripotent stem cells (hiPSC) derived from a PD patient carrying a duplication of the SNCA gene locus (SNCADupl) [9]. We further described a link between elevated aSyn levels and aggregation, disturbed tubulin distribution, and impaired neurite morphology These findings provide an insight into the molecular mechanism, through which degeneration of PD patient-derived neurons might occur
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