Neuroprotective effects of microRNA 124 in Parkinson's disease mice

Zhang, Fubo; Yao, Yu-Fang; Miao, Na; Wang, Nan; Xu, Xin; Yang, Chao-Ping

doi:10.1016/j.archger.2021.104588

Cited by 16 publications

(11 citation statements)

References 38 publications

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“…This relationship between NHLH1 and miR-124 has not been described before. miR-124 is a potent neurogenic microRNA that has been found to be downregulated in PD patients (99) and shown to be protective in PD animal models (100, 101). After determining the capacity of ABX464 in inducing miR-124 levels in neurons, the molecule was used to determine its effect during mDAN differentiation and as an attempt to rescue the NHLH1 KD.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation

Ramos

Ohnmacht

Lange

et al. 2023

Preprint

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Midbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinson's disease (PD). Many transcription factors (TFs) controlling human mDAN differentiation during development have been described, but much of the regulatory landscape remains undefined. Using a tyrosine hydroxylase (TH) iPSC reporter line, we have generated time series transcriptomic and epigenomic profiles of purified mDANs during differentiation. Integrative analysis predicted novel central regulators of mDAN differentiation and super-enhancers were used to prioritize key TFs. We find LBX1, NHLH1 and NR2F1/2 to be necessary for mDAN differentiation and show that overexpression of either LBX1 or NHLH1 can also improve mDAN specification. NHLH1 is necessary for the induction of neuronal miR-124, while LBX1 regulates cholesterol biosynthesis, possibly through mTOR signaling. Consistently, rapamycin treatment led to an inhibition of mDAN differentiation. Thus, our work reveals novel regulators of human mDAN differentiation.

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Section: Discussionmentioning

confidence: 99%

Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation

Ramos

Ohnmacht

Lange

et al. 2023

Preprint

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“…This relationship between NHLH1 and miR-124 has not been described before. miR-124 is a potent neurogenic microRNA that has been found to be downregulated in PD patients (Yang et al, 2021 ) and shown to be protective in PD animal models (Zhang et al, 2022 ; Saraiva et al, 2016 ). After determining the capacity of ABX464 in inducing miR-124 levels in neurons, the molecule was used to determine its effect during mDAN differentiation and as an attempt to rescue the NHLH1 KD.…”

Section: Discussionmentioning

confidence: 99%

Multiomics analysis identifies novel facilitators of human dopaminergic neuron differentiation

Gomez Ramos,

Ohnmacht,

de Lange

et al. 2023

EMBO Rep

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Midbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinson’s disease (PD). Many transcription factors (TFs) controlling human mDAN differentiation during development have been described, but much of the regulatory landscape remains undefined. Using a tyrosine hydroxylase (TH) human iPSC reporter line, we here generate time series transcriptomic and epigenomic profiles of purified mDANs during differentiation. Integrative analysis predicts novel regulators of mDAN differentiation and super-enhancers are used to identify key TFs. We find LBX1, NHLH1 and NR2F1/2 to promote mDAN differentiation and show that overexpression of either LBX1 or NHLH1 can also improve mDAN specification. A more detailed investigation of TF targets reveals that NHLH1 promotes the induction of neuronal miR-124, LBX1 regulates cholesterol biosynthesis, and NR2F1/2 controls neuronal activity.

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“…miRNA mimics and inhibitors have been used to change the endogenous levels of certain miRNAs and regulate cell function [ 63 , 64 ], as in the case of miR-124 [ 65 , 66 ]. The overexpression of miR-124 was shown to act as a neuroprotective factor in Parkinson’s disease [ 67 , 68 ] and in AD [ 62 , 69 ]. In human AD neuronal models with elevated levels of miR-124, we have shown by using an miR-124 mimic and inhibitor that an increase in miR-124 may be associated with mechanisms of defence and adaptation to the pathology [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

Intrathecal Injection of the Secretome from ALS Motor Neurons Regulated for miR-124 Expression Prevents Disease Outcomes in SOD1-G93A Mice

et al. 2022

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with short life expectancy and no effective therapy. We previously identified upregulated miR-124 in NSC-34-motor neurons (MNs) expressing human SOD1-G93A (mSOD1) and established its implication in mSOD1 MN degeneration and glial cell activation. When anti-miR-124-treated mSOD1 MN (preconditioned) secretome was incubated in spinal cord organotypic cultures from symptomatic mSOD1 mice, the dysregulated homeostatic balance was circumvented. To decipher the therapeutic potential of such preconditioned secretome, we intrathecally injected it in mSOD1 mice at the early stage of the disease (12-week-old). Preconditioned secretome prevented motor impairment and was effective in counteracting muscle atrophy, glial reactivity/dysfunction, and the neurodegeneration of the symptomatic mSOD1 mice. Deficits in corticospinal function and gait abnormalities were precluded, and the loss of gastrocnemius muscle fiber area was avoided. At the molecular level, the preconditioned secretome enhanced NeuN mRNA/protein expression levels and the PSD-95/TREM2/IL-10/arginase 1/MBP/PLP genes, thus avoiding the neuronal/glial cell dysregulation that characterizes ALS mice. It also prevented upregulated GFAP/Cx43/S100B/vimentin and inflammatory-associated miRNAs, specifically miR-146a/miR-155/miR-21, which are displayed by symptomatic animals. Collectively, our study highlights the intrathecal administration of the secretome from anti-miR-124-treated mSOD1 MNs as a therapeutic strategy for halting/delaying disease progression in an ALS mouse model.

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Neuroprotective effects of microRNA 124 in Parkinson's disease mice

Cited by 16 publications

References 38 publications

Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation

Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation

Multiomics analysis identifies novel facilitators of human dopaminergic neuron differentiation

Intrathecal Injection of the Secretome from ALS Motor Neurons Regulated for miR-124 Expression Prevents Disease Outcomes in SOD1-G93A Mice

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