Parkin mutation decreases neurite complexity and maturation in neurons derived from human fibroblasts

Pu, Jiali; Gao, Ting; Zheng, Ran; Fang, Yi; Ruan, Yang; Jin, Chong‐Yao; Shen, Ting; Tian, Jun; Zhang, Baorong

doi:10.1016/j.brainresbull.2020.03.006

Cited by 12 publications

(9 citation statements)

References 35 publications

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“…DA neurons derived from induced pluripotent stem cell lines from patients with parkin mutations have mitophagy and autophagy-lysosomal pathway defects [53,54], and the complexity and maturity of neurites is decreased by parkin mutations [55]. In the Drosophila model, PINK1 or parkin dysfunction can cause PARIS-dependent inhibition of PGC-1α and its downstream transcription factors NRF1 and TFAM in DA neurons, thereby blocking mitochondrial biogenesis [56].…”

Section: Discussionmentioning

confidence: 99%

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

Hsu

Hung

Tsai

et al. 2021

IJMS

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Parkinson’s disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Fritillaria thunbergii Miq that has antioxidant and anti-neuroinflammatory effects. We used Caenorhabditis elegans and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced reactive oxygen species production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin–proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.

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Section: Discussionmentioning

confidence: 99%

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

Hsu

Hung

Tsai

et al. 2021

IJMS

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“…The efficiency of converting Tuj1 + neurons was increased from 17.9 to 31.1% and the efficiency of converting TH + iDANs was increased from 8.3 to 15.4% ( Jiang et al, 2015 ). Pu et al (2020) used miR124 and p53-shRNA in a combination of transcription factors to reprogram the patient’s fibroblasts with Parkin gene mutation to the induced neurons. They found that mutations in the Parkin gene reduced the efficiency of converting somatic fibroblasts to TH + dopamine neurons (8.3 ± 0.6%), but did not affect the conversion efficiency of fibroblasts to total Tuj1 + neurons (18.2 ± 1.2%) ( Pu et al, 2020 ).…”

Section: Current Methods To Reprogram Somatic Fibroblasts To Neurons and Dopamine Neurons Directlymentioning

confidence: 99%

“… Pu et al (2020) used miR124 and p53-shRNA in a combination of transcription factors to reprogram the patient’s fibroblasts with Parkin gene mutation to the induced neurons. They found that mutations in the Parkin gene reduced the efficiency of converting somatic fibroblasts to TH + dopamine neurons (8.3 ± 0.6%), but did not affect the conversion efficiency of fibroblasts to total Tuj1 + neurons (18.2 ± 1.2%) ( Pu et al, 2020 ). De Gregorio et al (2018) used miR-34b/c combined with the transcription factors Ascl1 and NURR1 to reprogram fibroblasts into dopamine neurons directly with an efficiency of 19.5%.…”

Section: Current Methods To Reprogram Somatic Fibroblasts To Neurons and Dopamine Neurons Directlymentioning

confidence: 99%

Current Approaches and Molecular Mechanisms for Directly Reprogramming Fibroblasts Into Neurons and Dopamine Neurons

Han

Liu

Huang³

et al. 2021

Front. Aging Neurosci.

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Parkinson’s disease is mainly caused by specific degeneration of dopaminergic neurons (DA neurons) in the substantia nigra of the middle brain. Over the past two decades, transplantation of neural stem cells (NSCs) from fetal brain-derived neural stem cells (fNSCs), human embryonic stem cells (hESCs), and induced pluripotent stem cells (iPSCs) has been shown to improve the symptoms of motor dysfunction in Parkinson’s disease (PD) animal models and PD patients significantly. However, there are ethical concerns with fNSCs and hESCs and there is an issue of rejection by the immune system, and the iPSCs may involve tumorigenicity caused by the integration of the transgenes. Recent studies have shown that somatic fibroblasts can be directly reprogrammed to NSCs, neurons, and specific dopamine neurons. Directly induced neurons (iN) or induced DA neurons (iDANs) from somatic fibroblasts have several advantages over iPSC cells. The neurons produced by direct transdifferentiation do not pass through a pluripotent state. Therefore, direct reprogramming can generate patient-specific cells, and it can overcome the safety problems of rejection by the immune system and teratoma formation related to hESCs and iPSCs. However, there are some critical issues such as the low efficiency of direct reprogramming, biological functions, and risks from the directly converted neurons, which hinder their clinical applications. Here, the recent progress in methods, mechanisms, and future challenges of directly reprogramming somatic fibroblasts into neurons or dopamine neurons were summarized to speed up the clinical translation of these directly converted neural cells to treat PD and other neurodegenerative diseases.

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“…8 Localization of the most studied point mutations in the Parkin protein sequence related to oxidative stress defence, energy metabolism, and cell cycle regulation [157]. Neurons with parkin knockout exhibit reduced efficiency of reprogramming into DA neurons and a decrease in the total neurite length [158].…”

Section: G328ementioning

confidence: 99%

Multitasking guardian of mitochondrial quality: Parkin function and Parkinson’s disease

Kamienieva

Duszyński

Szczepanowska

2021

Transl Neurodegener

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The familial form of Parkinson’s disease (PD) is linked to mutations in specific genes. The mutations in parkin are one of the most common causes of early-onset PD. Mitochondrial dysfunction is an emerging active player in the pathology of neurodegenerative diseases, because mitochondria are highly dynamic structures integrated with many cellular functions. Herein, we overview and discuss the role of the parkin protein product, Parkin E3 ubiquitin ligase, in the cellular processes related to mitochondrial function, and how parkin mutations can result in pathology in vitro and in vivo.

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Parkin mutation decreases neurite complexity and maturation in neurons derived from human fibroblasts

Cited by 12 publications

References 35 publications

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

Current Approaches and Molecular Mechanisms for Directly Reprogramming Fibroblasts Into Neurons and Dopamine Neurons

Multitasking guardian of mitochondrial quality: Parkin function and Parkinson’s disease

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