Dysregulation of autophagy and mitochondrial function in Parkinson’s disease

Bao, Wei; Abraham, Neeta A.; Gao, Guodong; Yang, Qian

doi:10.1186/s40035-016-0065-1

Cited by 83 publications

(64 citation statements)

References 105 publications

(112 reference statements)

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“…In this study, we found that celastrol (1) increases protein levels of PINK1 and DJ-1 but represses LRRK2 expression, (2) enhances MAPK/ERK activation, and (3) celastrol maintains mitochondrial membrane potential and ATP production under MPP + treatment. Increasing evidence suggests that PINK1 and DJ-1 are essential for mitochondrial quality control [40]. DJ-1 overexpression induces ERK-dependent mitophagy and protects against rotenone-induced apoptosis [33].…”

Section: Discussionmentioning

confidence: 99%

Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy

Lin

Chen

et al. 2019

Antioxidants

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Parkinson’s disease (PD) is a neurodegenerative disease, which is associated with mitochondrial dysfunction and abnormal protein accumulation. No treatment can stop or slow PD. Autophagy inhibits neuronal death by removing damaged mitochondria and abnormal protein aggregations. Celastrol is a triterpene with antioxidant and anti-inflammatory effects. Up until now, no reports have shown that celastrol improves PD motor symptoms. In this study, we used PD cell and mouse models to evaluate the therapeutic efficacy and mechanism of celastrol. In the substantia nigra, we found lower levels of autophagic activity in patients with sporadic PD as compared to healthy controls. In neurons, celastrol enhances autophagy, autophagosome biogenesis (Beclin 1↑, Ambra1↑, Vps34↑, Atg7↑, Atg12↑, and LC3-II↑), and mitophagy (PINK1↑, DJ-1↑, and LRRK2↓), and these might be associated with MPAK signaling pathways. In the PD cell model, celastrol reduces MPP+-induced dopaminergic neuronal death, mitochondrial membrane depolarization, and ATP reduction. In the PD mouse model, celastrol suppresses motor symptoms and neurodegeneration in the substantia nigra and striatum and enhances mitophagy (PINK1↑ and DJ-1↑) in the striatum. Using MPP+ to induce mitochondrial damage in neurons, we found celastrol controls mitochondrial quality by sequestering impaired mitochondria into autophagosomes for degradation. This is the first report to show that celastrol exerts neuroprotection in PD by activating mitophagy to degrade impaired mitochondria and further inhibit dopaminergic neuronal apoptosis. Celastrol may help to prevent and treat PD.

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Section: Discussionmentioning

confidence: 99%

Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy

Lin

Chen

et al. 2019

Antioxidants

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“…Major features of mitochondrial dysfunction in PD include ROS overproduction, ATP depletion, mitochondrial DNA depletion, and caspase release. Mitochondrial toxins rotenone and MPTP can impair the mitochondrial function through inhibiting the activity of complex I, whereas suppression of complex I could result in abnormal OPA1 oxidation, which would subsequently lead to abnormality in mitochondrial structure and neurodegeneration of dopaminergic neurons …”

Section: Mitophagy and Neurodegenerative Diseasesmentioning

confidence: 99%

Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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Mitochondria are double‐membrane‐encircled organelles existing in most eukaryotic cells and playing important roles in energy production, metabolism, Ca 2+ buffering, and cell signaling. Mitophagy is the selective degradation of mitochondria by autophagy. Mitophagy can effectively remove damaged or stressed mitochondria, which is essential for cellular health. Thanks to the implementation of genetics, cell biology, and proteomics approaches, we are beginning to understand the mechanisms of mitophagy, including the roles of ubiquitin‐dependent and receptor‐dependent signals on damaged mitochondria in triggering mitophagy. Mitochondrial dysfunction and defective mitophagy have been broadly associated with neurodegenerative diseases. This review is aimed at summarizing the mechanisms of mitophagy in higher organisms and the roles of mitophagy in the pathogenesis of neurodegenerative diseases. Although many studies have been devoted to elucidating the mitophagy process, a deeper understanding of the mechanisms leading to mitophagy defects in neurodegenerative diseases is required for the development of new therapeutic interventions, taking into account the multifactorial nature of diseases and the phenotypic heterogeneity of patients.

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“…Importantly, mutation in PD‐associated genes such as Pink1 has also been shown to contribute to dysregulation of a number of these cellular processes including mitochondrial dysfunction (Wang et al . ).…”

mentioning

confidence: 97%

“…Oxidative stress has been shown to affect key processes such as nucleic acid stability, ion channels functionality, and structure and function of cellular proteins ultimately culminating in neuronal death (Uttara et al 2009;Zhao et al 2017). Importantly, mutation in PD-associated genes such as Pink1 has also been shown to contribute to dysregulation of a number of these cellular processes including mitochondrial dysfunction (Wang et al 2016).…”

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confidence: 99%

Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP⁺

Boonying

Joselin

Huang

et al. 2019

Journal of Neurochemistry

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Loss of function mutations in the PTEN‐induced putative kinase 1 (Pink1) gene have been linked with an autosomal recessive familial form of early onset Parkinson's disease (PD). However, the underlying mechanism(s) responsible for degeneration remains elusive. Presently, using co‐immunoprecipitation in HEK (Human embryonic kidney) 293 cells, we show that Pink1 endogenously interacts with FK506‐binding protein 51 (FKBP51 or FKBP5), FKBP5 and directly phosphorylates FKBP5 at Serine in an in vitro kinase assay. Both FKBP5 and Pink1 have been previously associated with protein kinase B (AKT) regulation. We provide evidence using primary cortical cultured neurons from Pink1‐deficient mice that Pink1 increases AKT phosphorylation at Serine 473 (Ser473) challenged by 1‐methyl‐4‐phenylpyridinium (MPP+) and that over‐expression of FKBP5 using an adeno‐associated virus delivery system negatively regulates AKT phosphorylation at Ser473 in murine‐cultured cortical neurons. Interestingly, FKBP5 over‐expression promotes death in response to MPP+ in the absence of Pink1. Conversely, shRNA‐mediated knockdown of FKBP5 in cultured cortical neurons is protective and this effect is reversed with inhibition of AKT signaling. In addition, shRNA down‐regulation of PH domain leucine‐rich repeat protein phosphatase (PHLPP) in Pink1 WT neurons increases neuronal survival, while down‐regulation of PHLPP in Pink1 KO rescues neuronal death in response to MPP+. Finally, using co‐immunoprecipitation, we show that FKBP5 interacts with the kinase AKT and phosphatase PHLPP. This interaction is increased in the absence of Pink1, both in Mouse Embryonic Fibroblasts (MEF) and in mouse brain tissue. Expression of kinase dead Pink1 (K219M) enhances FKBP5 interaction with both AKT and PHLPP. Overall, our results suggest a testable model by which Pink1 could regulate AKT through phosphorylation of FKBP5 and interaction of AKT with PHLPP. Our results suggest a potential mechanism by which PINK1‐FKBP5 pathway contributes to neuronal death in PD. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

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Dysregulation of autophagy and mitochondrial function in Parkinson’s disease

Cited by 83 publications

References 105 publications

Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy

Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy

Mechanisms and roles of mitophagy in neurodegenerative diseases

Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP⁺

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Dysregulation of autophagy and mitochondrial function in Parkinson’s disease

Cited by 83 publications

References 105 publications

Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy

Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy

Mechanisms and roles of mitophagy in neurodegenerative diseases

Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP+

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Product

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Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP⁺