Cell Biology of Parkin: Clues to the Development of New Therapeutics for Parkinson’s Disease

Patel, Jaimin; Panicker, Nikhil; Dawson, Valina L.; Dawson, Ted M.

doi:10.1007/s40263-022-00973-7

Cited by 6 publications

(8 citation statements)

References 208 publications

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“…The main function of parkin is E3 ubiquitin ligase, which is involved in the degradation pathway of specific ubiquitin-labeled proteins to proteasomes or lysosomes [ 25 ]. Additionally, when the mitochondria of cells are abnormal, parkin can recognize the specific protein PINK1 on the outer membrane and clear them by promoting mitophagy [ 26 ]. Furthermore, parkin can regulate apoptosis through mitochondria-dependent and -independent pathways [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

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Interaction of a Novel Alternatively Spliced Variant of HSD11B1L with Parkin Enhances the Carcinogenesis Potential of Glioblastoma: Peiminine Interferes with This Interaction

Hong

Tsai

et al. 2023

Cells

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Glioblastoma (GBM) is a primary brain tumor of unknown etiology. It is extremely aggressive, incurable and has a short average survival time for patients. Therefore, understanding the precise molecular mechanisms of this diseases is essential to establish effective treatments. In this study, we cloned and sequenced a splice variant of the hydroxysteroid-like 11-β dehydrogenase 1 gene (HSD11B1L) and named it HSD11B1L-181. HSD11 B1L-181 was specifically expressed only in GBM cells. Overexpression of this variant can significantly promote the proliferation, migration and invasion of GBM cells. Knockdown of HSD11B1L-181 expression inhibited the oncogenic potential of GBM cells. Furthermore, we identified the direct interaction of parkin with HSD11B1L-181 by screening the GBM cDNA expression library via yeast two-hybrid. Parkin is an RBR E3 ubiquitin ligase whose mutations are associated with tumorigenesis. Small interfering RNA treatment of parkin enhanced the proliferative, migratory and invasive abilities of GBM. Finally, we found that the alkaloid peiminine from the bulbs of Fritillaria thunbergii Miq blocks the interaction between HSD11B1L-181 and parkin, thereby lessening carcinogenesis of GBM. We further confirmed the potential of peiminine to prevent GBM in cellular, ectopic and orthotopic xenograft mouse models. Taken together, these findings not only provide insight into GBM, but also present an opportunity for future GBM treatment.

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, parkin can regulate apoptosis through mitochondria-dependent and -independent pathways [ 27 ]. Thus, mutations in parkin are linked with the death of dopamine neurons in Parkinson’s disease [ 26 ] and in various malignancies including GBM [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Interaction of a Novel Alternatively Spliced Variant of HSD11B1L with Parkin Enhances the Carcinogenesis Potential of Glioblastoma: Peiminine Interferes with This Interaction

Hong

Tsai

et al. 2023

Cells

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“…The report showed that loss-of-function mutations in parkin cause autosomal recessive PD. There is also evidence that parkin is inactivated in sporadic PD [ 65 ]. The loss of DA neurons accompanied by increased ZNF746 protein and decreased PGC-1α and mitochondrial biogenesis were found in the brains of PD patients with parkin mutations [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Chiisanoside Mediates the Parkin/ZNF746/PGC-1α Axis by Downregulating MiR-181a to Improve Mitochondrial Biogenesis in 6-OHDA-Caused Neurotoxicity Models In Vitro and In Vivo: Suggestions for Prevention of Parkinson’s Disease

Hsu,

Chen,

Gao

et al. 2023

Antioxidants

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The degeneration of dopamine (DA) neurons is known to be associated with defects in mitochondrial biogenesis caused by aging, environmental factors, or mutations in genes, leading to Parkinson’s disease (PD). As PD has not yet been successfully cured, the strategy of using small molecule drugs to protect and restore mitochondrial biogenesis is a promising direction. This study evaluated the efficacy of synthetic chiisanoside (CSS) identified in the leaves of Acanthopanax sessiliflorus to prevent PD symptoms. The results show that in the 6-hydroxydopamine (6-OHDA) model, CSS pretreatment can effectively alleviate the reactive oxygen species generation and apoptosis of SH-SY5Y cells, thereby lessening the defects in the C. elegans model including DA neuron degeneration, dopamine-mediated food sensitivity behavioral disorders, and shortened lifespan. Mechanistically, we found that CSS could restore the expression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α), a key molecule in mitochondrial biogenesis, and its downstream related genes inhibited by 6-OHDA. We further confirmed that this is due to the enhanced activity of parkin leading to the ubiquitination and degradation of PGC-1α inhibitor protein Zinc finger protein 746 (ZNF746). Parkin siRNA treatment abolished this effect of CSS. Furthermore, we found that CSS inhibited 6-OHDA-induced expression of miR-181a, which targets parkin. The CSS’s ability to reverse the 6-OHDA-induced reduction in mitochondrial biogenesis and activation of apoptosis was abolished after the transfection of anti-miR-181a and miR-181a mimics. Therefore, the neuroprotective effect of CSS mainly promotes mitochondrial biogenesis by regulating the miR-181a/Parkin/ZNF746/PGC-1α axis. CSS potentially has the opportunity to be developed into PD prevention agents.

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“…Another example of a neurological disease gene from Table 1 is PRKN , which is mutated in an autosomal recessive manner in juvenile parkinsonism. It encodes a 465‐amino acid‐long E3 ubiquitin ligase, and loss of this enzyme leads to defective control over levels of a number of proteins that ultimately leads to degeneration of dopaminergic neurons in the substantia nigra and early‐onset of Parkinson's disease 45 . A large set of mutations including deletions, frameshifts, and missense mutations have been observed in patients; curiously, gain‐of‐function has been attributed to some of the missense mutations 46,47 .…”

Section: Neurological Disease Gene Candidates For Humanization In Dro...mentioning

confidence: 99%

“…It encodes a 465-amino acid-long E3 ubiquitin ligase, and loss of this enzyme leads to defective control over levels of a number of proteins that ultimately leads to degeneration of dopaminergic neurons in the substantia nigra and early-onset of Parkinson's disease. 45 A large set of mutations including deletions, frameshifts, and missense mutations have been observed in patients; curiously, gain-of-function has been attributed to some of the missense mutations. 46,47 Mouse modeling of juvenile parkinsonism has been attempted by creating knockout animals, but the homozygous animals did not reveal any loss of dopaminergic neurons despite having moderate behavioral/motor deficits.…”

Section: Drosophilamentioning

confidence: 99%

Humanization for neurological disease modeling: A roadmap to increase the potential of Drosophila model systems

Katanaev

2023

Anim Models and Exp Med

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Neurological and neurodegenerative diseases plague our aging society, and have risen to become the leading cause of disability and the second leading cause of death worldwide. 1,2 Model organisms are widely used to study the molecular etiology of neurological diseases and to develop eventual treatments against them. 3 Despite the promise of non-vertebrate organisms such as Drosophila melanogaster in modeling neurological disease, 4,5 rodent models dominate this field of basic and translational research. In Switzerland alone, a country of ca. 8.7 million citizens, 0.9 million rodents (of which 0.7 million are mice) have been used for neurology disease-directed research in the period 2011-2021 (tv-statistik.ch/fr/statistiquesdynamiques). The insufficient adequacy of Drosophila disease models of human diseases is among the many reasons for the preferential use of mice versus fruit flies in neurology research. As elaborated here, this problem could be ameliorated by using the genetic humanization approach.

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Cell Biology of Parkin: Clues to the Development of New Therapeutics for Parkinson’s Disease

Cited by 6 publications

References 208 publications

Interaction of a Novel Alternatively Spliced Variant of HSD11B1L with Parkin Enhances the Carcinogenesis Potential of Glioblastoma: Peiminine Interferes with This Interaction

Interaction of a Novel Alternatively Spliced Variant of HSD11B1L with Parkin Enhances the Carcinogenesis Potential of Glioblastoma: Peiminine Interferes with This Interaction

Chiisanoside Mediates the Parkin/ZNF746/PGC-1α Axis by Downregulating MiR-181a to Improve Mitochondrial Biogenesis in 6-OHDA-Caused Neurotoxicity Models In Vitro and In Vivo: Suggestions for Prevention of Parkinson’s Disease

Humanization for neurological disease modeling: A roadmap to increase the potential of Drosophila model systems

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