CRISPR/Cas9-mediated PINK1 deletion leads to neurodegeneration in rhesus monkeys

Yang, Wenli; Liu, Yunbo; Tu, Zhuchi; Xiao, Cheng; Yan, Shihai; Ma, Xishan; Guo, Xiangyu; Chen, Xiusheng; Yin, Peng; Yang, Zhengyi; Su, Yang; Jiang, Tianzi; Li, Shihua; Qin, Chuan; Li, Shengbo Eben

doi:10.1038/s41422-019-0142-y

Cited by 65 publications

(83 citation statements)

References 12 publications

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“…Similar work was published earlier by Xiao-Jiang Li’s group(Yang et al, 2019), showing that CRISPR/Cas9 with paired sgRNAs enabled the generation of PINK1 knockout rhesus models via inducing a large deletion across exon 2 and4. We speculate that the large deletions generated in Li’s group permitted the RNA splicing from PINK1 exon 1 direct to exon 5, thus leading to non-sense mediated mRNA decay (NMD)(Brogna et al, 2009) and consequently eliminating protein translation.…”

Section: Discussionsupporting

confidence: 77%

MutatingPINK1gene by paired truncated sgRNA/Cas9-D10A in Cynomolgus Monkey

Chen

Kang

Yang

et al. 2020

Preprint

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Mutations of PINK1 cause early-onset Parkinson's disease (PD) with selective neurodegeneration in humans. However, current PINK1 knockout mouse and pig models are unable to recapitulate the typical neurodegenerative phenotypes observed in PD patients, indicating that it is essential to generate PINK1 disease models in non-human primates (NHPs) that are highly close to humans, to investigate the unique function of PINK1 in primate brains. Paired single guide RNA (sgRNA)/Cas9-D10A nickases and truncated sgRNA/Cas9, both enabling the reduction of the off-target effect without apparently compromising the on-target editing, are two optimized strategies in applying the CRISPR/Cas9 system to establish disease animal models. Here, we combined the two strategies and injected Cas9-D10A mRNA and two truncated sgRNAs into one-cell-stage cynomolgus zygotes to target PINK1 gene. We show precise and efficient gene editing of the target site in the three new born cynomolgus monkeys. The frame shift mutations of PINK1 in mutant fibroblasts leaded to the reduction of the mRNA, However, western-blot and immunofluorescence staining confirmed the PINK1 protein levels were comparable to that in the wild-type fibroblasts. We further reprogramed mutant fibroblast into induced pluripotent stem cells (iPSCs) and they show similar ability of differentiation into dopamine (DA) neurons. Taken together, our results showed that coinjection of Cas9-D10A nickase mRNA and sgRNA into one-cell-stage cynomolgus embryos enable the generation of human disease models in NHPs and the target editing by paired truncated sgRNA/Cas9-D10A in PINK1 gene exon 2 did not impact the protein expression.

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Section: Discussionsupporting

confidence: 77%

MutatingPINK1gene by paired truncated sgRNA/Cas9-D10A in Cynomolgus Monkey

Chen

Kang

Yang

et al. 2020

Preprint

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“…These studies also suggest there may be PINK1 independent mitophagy pathways yet to be eluded too. Recently, CRISPR/Cas9-mediated Pink1 deletion in rhesus macaques triggered severe neurodegeneration of the cortex, striatum and substantia nigra, with several new-borns dying shortly after birth [ 151 , 152 ]. These data suggest that in humans full PINK1 loss may lead to lethality in early development.…”

Section: Pink1/parkin In Neurodegenerationmentioning

confidence: 99%

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

Quinn

Moreira

Ambrósio

et al. 2020

acta neuropathol commun

260

136

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Mutations in the PTEN-induced kinase 1 (PINK1) and Parkin RBR E3 ubiquitin-protein ligase (PARKIN) genes are associated with familial forms of Parkinson’s disease (PD). PINK1, a protein kinase, and PARKIN, an E3 ubiquitin ligase, control the specific elimination of dysfunctional or superfluous mitochondria, thus fine-tuning mitochondrial network and preserving energy metabolism. PINK1 regulates PARKIN translocation in impaired mitochondria and drives their removal via selective autophagy, a process known as mitophagy. As knowledge obtained using different PINK1 and PARKIN transgenic animal models is being gathered, growing evidence supports the contribution of mitophagy impairment to several human pathologies, including PD and Alzheimer’s diseases (AD). Therefore, therapeutic interventions aiming to modulate PINK1/PARKIN signalling might have the potential to treat these diseases. In this review, we will start by discussing how the interplay of PINK1 and PARKIN signalling helps mediate mitochondrial physiology. We will continue by debating the role of mitochondrial dysfunction in disorders such as amyotrophic lateral sclerosis, Alzheimer’s, Huntington’s and Parkinson’s diseases, as well as eye diseases such as age-related macular degeneration and glaucoma, and the causative factors leading to PINK1/PARKIN-mediated neurodegeneration and neuroinflammation. Finally, we will discuss PINK1/PARKIN gene augmentation possibilities with a particular focus on AD, PD and glaucoma.

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“…However, overexpression of Parkin or PINK1 in Drosophila melanogaster leads to lifespan extension [ 354 , 355 ]. Furthermore, a recent study in rhesus monkeys that deleted PINK1 by CRISPR/Cas9 showed by MRI and EM significantly decreased gray matter and degenerated neurons in the cortex, substantia nigra and striatum in adult monkeys [ 356 , 357 ]. This suggests that there are species specific differences and studies in mice may not necessarily capture fully the significance of the PINK1/Parkin mitophagic pathway during aging.…”

Section: Mitochondrial Quality Controlmentioning

confidence: 99%

Intimate Relations—Mitochondria and Ageing

Webb¹,

Sideris²

2020

IJMS

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Mitochondrial dysfunction is associated with ageing, but the detailed causal relationship between the two is still unclear. We review the major phenomenological manifestations of mitochondrial age-related dysfunction including biochemical, regulatory and energetic features. We conclude that the complexity of these processes and their inter-relationships are still not fully understood and at this point it seems unlikely that a single linear cause and effect relationship between any specific aspect of mitochondrial biology and ageing can be established in either direction.

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CRISPR/Cas9-mediated PINK1 deletion leads to neurodegeneration in rhesus monkeys

Cited by 65 publications

References 12 publications

MutatingPINK1gene by paired truncated sgRNA/Cas9-D10A in Cynomolgus Monkey

MutatingPINK1gene by paired truncated sgRNA/Cas9-D10A in Cynomolgus Monkey

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

Intimate Relations—Mitochondria and Ageing

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