Mitochondrial dysfunction in Parkinsonian mesenchymal stem cells impairs differentiation

Plamena R Angelova,Mario Barilani,Christopher Lovejoy,Marta Dossena,Mariele Viganò,Agostino Seresini,Daniela Piga,Sonia Gandhi,Gianni Pezzoli,Andrey Y Abramov,Lorenza Lazzari

doi:10.1016/j.redox.2017.10.016

Abstract

Sporadic cases account for 90–95% of all patients with Parkinson's Disease (PD). Atypical Parkinsonism comprises approximately 20% of all patients with parkinsonism. Progressive Supranuclear Palsy (PSP) belongs to the atypical parkinsonian diseases and is histopathologically classified as a tauopathy. Here, we report that mesenchymal stem cells (MSCs) derived from the bone marrow of patients with PSP exhibit mitochondrial dysfunction in the form of decreased membrane potential and inhibited NADH-dependent respiration. Furthermore, mitochondrial dysfunction in PSP-MSCs led to a significant increase in mitochondrial ROS generation and oxidative stress, which resulted in decrease of major cellular antioxidant GSH. Additionally, higher basal rate of mitochondrial degradation and lower levels of biogenesis were found in PSP-MSCs, together leading to a reduction in mitochondrial mass. This phenotype was biologically relevant to MSC stemness properties, as it heavily impaired their differentiation into adipocytes, which mostly rely on mitochondrial metabolism for their bioenergetic demand. The defect in adipogenic differentiation was detected as a significant impairment of intracellular lipid droplet formation in PSP-MSCs. This result was corroborated at the transcriptional level by a significant reduction of PPARγ and FABP4 expression, two key genes involved in the adipogenic molecular network. Our findings in PSP-MSCs provide new insights into the etiology of ‘idiopathic’ parkinsonism, and confirm that mitochondrial dysfunction is important to the development of parkinsonism, independent of the type of the cell.

Highlights

In the framework of neurodegenerative diseases, “sporadic” or “idiopathic” forms of Parkinson's Disease (PD) and to a greater extent atypical parkinsonian disorders, have been largely neglected due to the absence of a clear and unequivocal genetic background, such as in familial monogenic PD [1]
Within a phase I clinical study we evaluated the safety of autologous bone marrow mesenchymal stem cell (MSC) administration to Progressive Supranuclear Palsy (PSP) patients to stabilize the progression of the disease, thanks to mesenchymal stem cells (MSCs) paracrine properties [14]
Using tetramethylrhodamine methylester (TMRM) as a fluorescent indicator of ΔΨm, we found that PSP-MSCs showed significantly decreased basal ΔΨm (Fig. 1, A and A1)

Summary

Introduction

In the framework of neurodegenerative diseases, “sporadic” or “idiopathic” forms of Parkinson's Disease (PD) and to a greater extent atypical parkinsonian disorders, have been largely neglected due to the absence of a clear and unequivocal genetic background, such as in familial monogenic PD [1]. A major involvement of mitochondria in the pathological mechanisms of diverse neurodegenerative diseases is becoming increasingly evident [8]. This aspect has already been proven useful at the clinical level, relying on glucose tissue distribution to differentiate Parkinsonism subtypes through metabolic brain imaging [9]

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Results

Conclusion