Microtubule Alterations Occur Early in Experimental Parkinsonism and The Microtubule Stabilizer Epothilone D Is Neuroprotective

Abstract

The role of microtubule (MT) dysfunction in Parkinson's disease is emerging. It is still unknown whether it is a cause or a consequence of neurodegeneration. Our objective was to assess whether alterations of MT stability precede or follow axonal transport impairment and neurite degeneration in experimental parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57Bl mice. MPTP induced a time- and dose-dependent increase in fibres with altered mitochondria distribution, and early changes in cytoskeletal proteins and MT stability. Indeed, we observed significant increases in neuron-specific βIII tubulin and enrichment of deTyr tubulin in dopaminergic neurons. Finally, we showed that repeated daily administrations of the MT stabilizer Epothilone D rescued MT defects and attenuated nigrostriatal degeneration induced by MPTP. These data suggest that alteration of ΜΤs is an early event specifically associated with dopaminergic neuron degeneration. Pharmacological stabilization of MTs may be a viable strategy for the management of parkinsonism.

Is the Regulation of Microtubule Stability at the Crossroad Between Aging and Disease of Dopaminergic neurons?

“…The above described MT-based neuronal defects can be counteracted by the administration of MT-stabilizing agents, as already suggested [19,39] and demonstrated in many of the studies above reported [26,28,34]. A reliable alternative can be the fine modulation of MT acetylation, which seems to be tightly associated to axonal transport and locomotor defects [16,36,38].…”

“…Although the identity of the real culprit of the pathology is still debated, in the recent years it is becoming ever clearer that MT destabilization is an early event in experimental and human models of PD, and many of the studies reported below strongly suggest that it can be followed by the hyper-stabilization of MTs, which could lead to detrimental side effects. Indeed, during the last decade, we have demonstrated that MPP + , the metabolite of the PD-inducing toxin MPTP, acts as a catastrophe promoter, leading to the earlier MT destabilization and to a later excessive accumulation of tubulin PTMs associated to stable MTs (detyrosination and acetylation), in vitro as well as in vivo [24][25][26]. Similarly, 6-hydroxydopamine elicits significant alterations in MT dynamics, including reduction in MT growth rate and overload of α tubulin acetylation [27].…”

GRP78 clustering at the cell surface of neurons transduces the action of exogenous alpha-synuclein

“…The microtubular cytoskeleton has already been identified as a target for therapy in neurodegenerative diseases; 39,40 here, we propose that drugs acting on the actin cytoskeleton have potential use in the treatment of PD. In addition, as depletion of the medium from Syn was sufficient to reduce the propagation of cytoskeletal pathology, the reduction of the circulating levels of Syn might be an additional therapeutic target at early stage of the disease, as suggested and reviewed in.…”

“…Denatured and non denatured Syns affected the morphology of actin cytoskeleton in a similar way, inducing both a significant increase in actin protrusion areas and resistance to depolymerization (Figures 2a and b). To exclude the possibility that the effect of Syn was due to fibril formation, we used three distinct Syn peptides: P34 (aa [34][35][36][37][38][39][40][41][42][43][44][45], that is, the glycosphingolipid-binding domain of Syn, P61 (aa 61-78), that is, the cholesterol-binding domain of Syn that has been shown to aggregate 20,21 and P12 (aa 12-23), a peptide with no recognized function. None of these peptides determined measurable effects on cytoskeleton stabilization, suggesting that the whole protein, monomeric and unfolded, is required for its action on microfilaments (Figures 2a and b).…”

Chemical Modulators of Protein Misfolding, Neurodegeneration and Tau

“…Surprisingly, low epoD dosages reduce the hyperdynamicity of MTs and cognitive deficits, while higher dosages are ineffective [45]. EpoD (1 mg/kg/daily, i.p., 4 days 100 ratios after toxin treatment) rescues MT defects, restores axonal transport, and attenuates nigrostriatal degeneration in a Parkinson's disease (PD) model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [46]. Unexpectedly, Phase Ib clinical evaluation of epoD (0.003-0.3 mg/kg/weekly, intravenously/i.v., 9 weeks) shows sub-optimal pharmacodynamics (PDy) levels [47].…”