Microtubule Destabilization Is Shared by Genetic and Idiopathic Parkinson’s Disease Patient Fibroblasts

Abstract

Data from both toxin-based and gene-based models suggest that dysfunction of the microtubule system contributes to the pathogenesis of Parkinson’s disease, even if, at present, no evidence of alterations of microtubules in vivo or in patients is available. Here we analyze cytoskeleton organization in primary fibroblasts deriving from patients with idiopathic or genetic Parkinson’s disease, focusing on mutations in parkin and leucine-rich repeat kinase 2. Our analyses reveal that genetic and likely idiopathic pathology affects cytoskeletal organization and stability, without any activation of autophagy or apoptosis. All parkinsonian fibroblasts have a reduced microtubule mass, represented by a higher fraction of unpolymerized tubulin in respect to control cells, and display significant changes in microtubule stability-related signaling pathways. Furthermore, we show that the reduction of microtubule mass is so closely related to the alteration of cell morphology and behavior that both pharmacological treatment with microtubule-targeted drugs, and genetic approaches, by transfecting the wild type parkin or leucine-rich repeat kinase 2, restore the proper microtubule stability and are able to rescue cell architecture. Taken together, our results suggest that microtubule destabilization is a point of convergence of genetic and idiopathic forms of parkinsonism and highlight, for the first time, that microtubule dysfunction occurs in patients and not only in experimental models of Parkinson’s disease. Therefore, these data contribute to the knowledge on molecular and cellular events underlying Parkinson’s disease and, revealing that correction of microtubule defects restores control phenotype, may offer a new therapeutic target for the management of the disease.

Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson's disease cells

“…Therefore, it is unlikely that L-Dopa induced hyper-phosphorylation of GSK3α. Previous data from Cartelli et al (2012) showed that GSK3β phosphorylation at Ser9 is reduced in fibroblasts of sporadic PD patients, but no further information on GSK3α (Ser21) phosphorylation in PD fibroblasts is available in the literature. Therefore, on the basis of our experimental data the exact nature of this finding remains difficult to explain.…”

α-Tubulin Tyrosination and CLIP-170 Phosphorylation Regulate the Initiation of Dynein-Driven Transport in Neurons

“…There is also a lower density of microtubules in the distal axon relative to the axon shaft, increasing the distance required for diffusion to microtubules. Further, decreased microtubule stability is associated with neurodegenerative diseases (Cartelli et al 2012; Esteves et al 2010), and tubulin tyrosine ligase expression may decrease with age (Gabius et al, 1983); these changes are predicted to further decrease binding efficiency. Importantly, the mechanisms regulating transport initiation described here suggest potential therapeutic approaches.…”

Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC α-synuclein transgenic rat model of Parkinson's disease

“…While the number of early DCX+ cells in the HC was even increased, the proportion of intermediate neuroblasts was significantly reduced in BAC alpha-synuclein rats, suggesting a particular impact of α-syn on young neurons during outgrowth of their processes. Interestingly, accumulating and/or oligomerized α-syn may destabilize microtubule cytoskeleton (Cartelli et al, 2012), thereby proportionally damaging intermediate and late-stage neuroblasts. Furthermore, selective activation of 5-HT 1A or 1B is required to promote neurite outgrowth and branching (Persico et al, 2006).…”