Distinct multilevel misregulations of Parkin and PINK1 revealed in cell and animal models of TDP-43 proteinopathy

Sun, Xing; Duan, Yongjia; Qin, Caixia; Li, Jian-Chiuan; Duan, Gang; Deng, Xue; Ni, Jiangxia; Cao, Xu; Ke, Xiang; Tian, Kuili; Chen, Chun Hong; Li, Ang; Fang, Yanshan

doi:10.1038/s41419-018-1022-y

Cited by 42 publications

(43 citation statements)

References 59 publications

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“…TDP-43 was found to govern Parkin mRNA levels in both an intron-mediated and intron-independent manner. While TDP-43 did not regulate Pink1 at the RNA level, its overexpression led to the cytosolic accumulation of cleaved PINK1 due to the impairment of the ubiquitin–proteasome system [ 46 ]. In stress conditions, such as ageing, this accumulation of cleaved PINK1 leading to reduced mitochondrial activity may be a risk factor promoting neurodegeneration.…”

Section: Pink1/parkin In Neurodegenerationmentioning

confidence: 99%

“…In stress conditions, such as ageing, this accumulation of cleaved PINK1 leading to reduced mitochondrial activity may be a risk factor promoting neurodegeneration. Lastly, Sun et al [ 46 ] found that by ameliorating the misregulation of PINK1 or PARKIN by their down or up-regulation, respectively, leads to suppression of the degenerative phenotypes observed in a TDP-43 proteinopathy fly model.…”

Section: Pink1/parkin In Neurodegenerationmentioning

confidence: 99%

“…However, there are several other causative genes for PD linked to mitochondrial dysregulation, including LRRK2, DJ1, ATP13A2 and SCNA, in addition to other PD risk genes [ 32 – 45 ]. Furthermore, dysregulation of PINK1/PARKIN signalling has been associated with amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), as well as eye diseases, such as age-related macular degeneration (AMD), and is associated with retinal degeneration [ 46 – 51 ]. Efforts for the amelioration of mitochondrial dysfunction through lentiviral and adeno-associated viral (AAV) mediated PINK1 and PARKIN gene augmentation therapeutics show promise (Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

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PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

Quinn

Moreira

Ambrósio

et al. 2020

acta neuropathol commun

282

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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Section: Pink1/parkin In Neurodegenerationmentioning

confidence: 99%

Section: Pink1/parkin In Neurodegenerationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

Quinn

Moreira

Ambrósio

et al. 2020

acta neuropathol commun

282

136

View full text Add to dashboard Cite

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“…Dopaminergic overexpression of parkin or PINK1 prevents the loss of DA neurons and rescues climbing defects in the PARIS transgenic flies ( Fig. 3a-d, Additional file 9, Targeted knockdown of either parkin or PINK1 using specific shRNA lines [48][49][50] in the DA neurons leads to loss of DA neurons and climbing defects and further exacerbates these dopaminergic phenotypes in the PARIS overexpressing flies ( Fig. 3a-d Figure S2 and Additional file 13, Figure S3 Immunoblot analysis reveals that dopaminergic knockdown of parkin or PINK1 leads to marked accumulation of PARIS whereas PARIS levels are significantly decreased in flies overexpressing parkin or PINK1 (Fig.…”

Section: Parkin Pink1 and Pgc-1α Rescue Dopaminergic Neuron Loss Caumentioning

confidence: 99%

PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of parkin or PINK1 deficiency

Pirooznia

Yuan

Khan

et al. 2020

Mol Neurodegeneration

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Background: Mutations in PINK1 and parkin cause autosomal recessive Parkinson's disease (PD). Evidence placing PINK1 and parkin in common pathways regulating multiple aspects of mitochondrial quality control is burgeoning. However, compelling evidence to causatively link specific PINK1/parkin dependent mitochondrial pathways to dopamine neuron degeneration in PD is lacking. Although PINK1 and parkin are known to regulate mitophagy, emerging data suggest that defects in mitophagy are unlikely to be of pathological relevance. Mitochondrial functions of PINK1 and parkin are also tied to their proteasomal regulation of specific substrates. In this study, we examined how PINK1/parkin mediated regulation of the pathogenic substrate PARIS impacts dopaminergic mitochondrial network homeostasis and neuronal survival in Drosophila. Methods: The UAS-Gal4 system was employed for cell-type specific expression of the various transgenes. Effects on dopamine neuronal survival and function were assessed by anti-TH immunostaining and negative geotaxis assays. Mitochondrial effects were probed by quantitative analysis of mito-GFP labeled dopaminergic mitochondria, assessment of mitochondrial abundance in dopamine neurons isolated by Fluorescence Activated Cell Sorting (FACS) and qRT-PCR analysis of dopaminergic factors that promote mitochondrial biogenesis. Statistical analyses employed two-tailed Student's T-test, one-way or two-way ANOVA as required and data considered significant when P < 0.05. Results: We show that defects in mitochondrial biogenesis drive adult onset progressive loss of dopamine neurons and motor deficits in Drosophila models of PINK1 or parkin insufficiency. Such defects result from PARIS dependent repression of dopaminergic PGC-1α and its downstream transcription factors NRF1 and TFAM that cooperatively promote mitochondrial biogenesis. Dopaminergic accumulation of human or Drosophila PARIS recapitulates these neurodegenerative phenotypes that are effectively reversed by PINK1, parkin or PGC-1α overexpression in vivo. To our knowledge, PARIS is the only co-substrate of PINK1 and parkin to specifically accumulate in the DA neurons and cause neurodegeneration and locomotor defects stemming from disrupted dopamine signaling.

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“…Nevertheless, CHCHD10 S59L expression induced PINK1 stabilization in mitochondria without strong disruption of mitochondrial membrane potential, and genetic/pharmacologic inhibition of PINK1 mitigated CHCHD10 S59L -induced toxicity. Reducing PINK1 or parkin-mediated pathways are beneficial in in vivo disease models of SOD1, FUS, and TARDBP mutations (55)(56)(57). We demonstrated that MFN2 agonists enhanced ATP production in flies expressing C9ORF72 with GGGGCC repeats.…”

Section: Discussionmentioning

confidence: 80%

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Baek

Choe

Dorn³

et al. 2019

Preprint

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†Authors contributed equally.One Sentence Summary: Inhibition of TDP-43 mitochondrial translocation or PINK1 kinase activity mitigates CHCHD10 S59L -mediated mitochondrial toxicity. AbstractMutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) are a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS-FTD). To elucidate how mutations in CHCHD10 induce disease, we generated a Drosophila melanogaster model of CHCHD10-mediated ALS-FTD. Expression of CHCHD10 S59L in Drosophila caused gain-offunction toxicity in eyes, motor neurons, and muscles, in addition to mitochondrial defects in flies and HeLa cells. TDP-43 and PINK1 formed two axes, driving the mutant-dependent phenotypes. CHCHD10 S59L expression increased TDP-43 insolubility and mitochondrial translocation. Blocking mitochondrial translocation with a peptide inhibitor reduced CHCHD10 S59L -mediated toxicity. PINK1 knockdown rescued CHCHD10 S59L -mediated phenotypes in Drosophila and HeLa cells. The two PINK1 substrates mitofusin and mitofilin were genetic modifiers of this phenotype. Mitofusin agonists reversed the CHCHD10 S59Linduced phenotypes in Drosophila and HeLa cells and increased ATP production in Drosophila expressing C9orf72 with expanded GGGGCC repeats. Two peptides inhibitors of PINK1 mitigated the mitochondrial defects introduced by CHCHD10 S59L expression. These findings indicate that TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways by CHCHD10 S59L generate dominant toxicity. Therefore, inhibiting PINK1 activity may provide a therapeutic strategy for CHCHD10-associated disease.

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Distinct multilevel misregulations of Parkin and PINK1 revealed in cell and animal models of TDP-43 proteinopathy

Cited by 42 publications

References 59 publications

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of parkin or PINK1 deficiency

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

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Distinct multilevel misregulations of Parkin and PINK1 revealed in cell and animal models of TDP-43 proteinopathy

Cited by 42 publications

References 59 publications

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of parkin or PINK1 deficiency

Dominant toxicity of ALS–FTD-associated CHCHD10S59L is mediated by TDP-43 and PINK1

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Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1