Is microtubule dynamics imbalance an early event in MPTP-induced neurodegeneration?

The molecular pathways implicated in neurodegenerative disorders are gradually being elucidated and several culprits including accumulation of aberrant or misfolded proteins, mitochondrial injury, oxidative and nitrosative stress, and failure of axonal and dendritic transport have been identified. However, understanding the primary degenerative event still remains a major challenge. Dysfunction of microtubule (MT) system is emerging as a novel contributing factor in Parkinson’s disease (PD). We reported earlier that MPP+, the toxic metabolite of the parkinsonism producing neurotoxin MPTP, binds specifically to tubulin and affects MT dynamics in vitro and in NGF-differentiated PC12 cells. Here we investigated whether alteration in MT dynamics could precede or follow axonal transport impairment and mitochondria dysfunction that are known pathogenetic mechanisms in MPP+ neurotoxicity. By time lapse imaging of PC12 cells expressing the MT-associated protein EB3-GFP, we show a significant reduction of MT dynamics following exposure to MPP+. The alteration of MT dynamics precedes the impairment of axonal transport and also ATP depletion, suggesting that it is an early event in MPP+-induced neurodegeneration. In order to validate the notion that dysfunction of MT dynamics occurs at the beginning of pathogenesis, we studied an animal model of experimental parkinsonism. We have analysed post-translational modifications of tubulin known to be associated with differently dynamic MTs and show an enrichment in stable MTs in the corpus striatum of MPTP-treated mice at early time points, before the onset of dopaminergic nigrostriatal system degeneration (i.e. reduction of TH levels). These results suggest that MTs are critical target of MPTP/MPP+. Since MT dynamics are crucial in MT biological functions, we hypothesise that the altered dynamic behaviour of MTs could represent a novel pathogenic pathway triggering neuronal cell death in PD.