Mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell models of Parkinson's disease

Bose, Arup; Beal, M. Flint

doi:10.1111/ejn.14264

Cited by 40 publications

(25 citation statements)

References 48 publications

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“…The symptoms of PD are caused by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) resulting in a decrease of dopamine (DA) levels in the striatum. Mitochondrial dysfunction and its related oxidative stress and inflammation are common features in PD patient brain samples, PD iPSC-derived neurons, and/or PD animal models [11,12,41,42]. To note, pathological studies in the substantia nigra regions from 6 patients suggest that Complex I deficiency did not correlate with parkinsonism [43].…”

Section: Defective Mitophagy and Imbalanced Mitochondria-derived Vesimentioning

confidence: 99%

Mitophagy and Neuroprotection

Lou

Palikaras

Lautrup

et al. 2020

Trends in Molecular Medicine

312

183

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Neurodegenerative diseases are strongly age-related and currently cannot be cured, with a surge of patient numbers in the coming decades in view of the emerging worldwide ageing population, bringing healthcare and socioeconomic challenges. Effective therapies are urgently needed, and are dependent on new etiological mechanisms. In neurons, efficient clearance of damaged mitochondria, through the highly evolutionary conserved cellular process termed mitophagy, plays a fundamental role in mitochondrial and metabolic homeostasis, energy supply, neuronal survival and health. Conversely, defective mitophagy leads to accumulation of damaged mitochondria and cellular dysfunction, contributing to ageing and age-predisposed neurodegeneration. Here, we discuss the contribution of defective mitophagy in these diseases, and underlying molecular mechanisms, and highlight novel therapeutics based on new discovered mitophagy-inducing strategies.

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Section: Defective Mitophagy and Imbalanced Mitochondria-derived Vesimentioning

confidence: 99%

Mitophagy and Neuroprotection

Lou

Palikaras

Lautrup

et al. 2020

Trends in Molecular Medicine

312

183

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“…Although the precise pathogenesis of PD still remains elusive, several studies demonstrate that mitochondrial dysfunction and oxidative damage play the important roles in PD pathogenesis [5–7]. It has been revealed that 25–30% of PD patients have significant deficiency of mitochondrial complex I and increased reactive oxygen species (ROS) levels [8].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of protocatechuic aldehyde through PLK2/p-GSK3β/Nrf2 signaling pathway in both in vivo and in vitro models of Parkinson's disease

Guo

Zhu

Wang

et al. 2019

Aging

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Mitochondrial dysfunction and oxidative damage are closely related to the pathogenesis of Parkinson's disease (PD). The pharmacological mechanism of protocatechuic aldehyde (PCA) for PD treatment have retained unclear. The purposes of the present study were to clarify the neuroprotective effects of post-treatment of PCA for PD treatment by mitigating mitochondrial dysfunction and oxidative damage, and to further determine whether its effects were mediated by the polo-like kinase 2/phosphorylated glycogen synthase kinase 3 β/nuclear factor erythroid-2-related factor 2 (PLK2/p-GSK3β/Nrf2) pathways. We found that PCA improved 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced behavioral deficits and dopaminergic cell loss. Moreover, PCA increased the expressions of PLK2, p-GSK3β and Nrf2, following the decrease of α-synuclein (α-Syn) in MPTP-intoxicated mice. Cell viability was increased and the apoptosis rate was reduced by PCA in 1-methyl-4-phenylpyridinium iodide (MPP+)-incubated cells. Mitochondrial membrane potential (MMP), mitochondrial complex I activity and reactive oxygen species (ROS) levels in MPP+-incubated cells were also ameliorated by treatment with PCA. The neuroprotective effects of PCA were abolished by inhibition or knockdown of PLK2, whereas overexpression of PLK2 strengthened the protection of PCA. Furthermore, GSK3β and Nrf2 were involved in PCA-induced protection. These results indicated that PCA has therapeutic effects on PD by the PLK2/p-GSK3β/Nrf2 pathway.

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“…Furthermore, other studies have found increased vulnerability to oxidative stress, higher levels of mtDNA damage, and impaired mitochondrial movement as a result of the G2019S mutation, indicating compromised mitochondrial function (Cooper et al, 2012, Sanders et al, 2014, Hsieh et al, 2016, Schwab et al, 2017, Bose and Beal, 2019. Mitochondrial function alterations have in turn been shown to affect the plasticity of synapses and morphology of neurites as the availability of mitochondria is both essential and limiting for the support and maintenance of these structures (Li et al, 2004).…”

Section: Unveiling Different Network Stress Responses Through Transiementioning

confidence: 99%

Structural and functional alterations associated with the LRRK2 G2019S mutation revealed in structured human neural networks

Valderhaug

Ramstad

Wijdeven

et al. 2020

Preprint

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Running titleStructure and function in engineered human LRRK2 networks Total number of pages: 40 Total number of words: (i) whole manuscript: 8062; (ii) abstract: 235 AbstractMutations in the LRRK2 gene have been widely linked to Parkinson ś disease. The G2019S variant has been shown to contribute uniquely to both familial and sporadic forms of the disease. LRRK2-related mutations have been extensively studied, yet the wide variety of cellular and network events directly or indirectly related to these mutations remain poorly understood. In this study, we structured multi-nodal human neural networks carrying the G2019S mutation using custom-designed microfluidic chips coupled to microelectrode-arrays. By applying live imaging approaches, immunocytochemistry and computational modelling, we have revealed alterations in both the structure and function of the resulting neural networks when compared to controls. We provide first evidence of increased neuritic density associated with the G2019S LRRK2 mutation, while previous studies have found either a strong decrease, or no change, compared to controls. Additionally, we corroborate previous findings regarding increased baseline network activity compared to control neural networks. Furthermore, we can reveal additional network alterations attributable to the specific mutation by selectively inducing transient overexcitation to confined parts of the structured multi-nodal networks. These alterations, which we were able to capture both at the micro-and mesoscale manifested as differences in relative network activity and correlation, as well as in mitochondria activation, neuritic remodelling, and synaptic alterations. Our study thus provides important new insights into early signs of neural network pathology significantly expanding upon the current knowledge relating to the G2019S Parkinson's disease mutation.

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Mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell models of Parkinson's disease

Cited by 40 publications

References 48 publications

Mitophagy and Neuroprotection

Mitophagy and Neuroprotection

Neuroprotective effects of protocatechuic aldehyde through PLK2/p-GSK3β/Nrf2 signaling pathway in both in vivo and in vitro models of Parkinson's disease

Structural and functional alterations associated with the LRRK2 G2019S mutation revealed in structured human neural networks

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