Upregulation of the p53-p21 pathway by G2019S LRRK2 contributes to the cellular senescence and accumulation of α-synuclein

Ho, Dong Hwan; Seol, Wongi; Son, Ilhong

doi:10.1080/15384101.2019.1577666

Cited by 28 publications

(25 citation statements)

References 38 publications

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“…P53 can mediate cell response to DNA damage, replicative aging due to telomere shortening, as well as stress-induced premature senescence. Its downstream factor p21 can inhibit CDK2 and CDK4, rendering them unable to phosphorylate pRB [19,20]. The resultant hypo-phosphorylated pRB can bind to E2F and prevent it from binding to target genes, thereby prohibiting cells from entering the S phase.…”

Section: Influence Of Curcumin On Cellular Senescencementioning

confidence: 99%

Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells

Tuan¹,

Wu²,

Rudaisat³

et al. 2020

J. Cancer

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Our study explored the tumor-suppressive effect of curcumin on cervical cancer cells. Cervical cancer is one of the most common cancers among women worldwide. Acquired resistance to chemotherapeutics and toxicity of such drugs has undermined the effectiveness of cervical cancer treatments. Therefore, the identification of novel chemotherapeutics is key to improving the survival of patients with cervical cancer. Curcumin has been shown to have various bioactivities, including antioxidant and antitumor effects; however, its effect on cervical cancer remains elusive. Here, we used the SiHa human cervical cancer cell line to test various concentrations of curcumin on the proliferation and apoptosis of cervical cancer cells. The involvement of autophagy and reactive oxygen species (ROS) in these effects were also tested by using specific autophagy inhibitors and ROS scavengers. Our results showed that curcumin induced ROS accumulation, apoptosis, autophagy, cell cycle arrest, and cellular senescence accompanied by upregulation of p53 and p21 proteins in SiHa cells.

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Section: Influence Of Curcumin On Cellular Senescencementioning

confidence: 99%

Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells

Tuan¹,

Wu²,

Rudaisat³

et al. 2020

J. Cancer

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“…Follow-up experiments to deplete microglia after Satb1 reduction would conclusively demonstrate whether or not Cdkn1a-expressing dopaminergic neurons fulfill the criterion of apoptosis resistance in neuronal senescence. Indeed, elevated p21 expression induced apoptosis in vitro, indicating that it may not confer neuronal apoptosis resistance [ 77 ]. Nevertheless, the study by Riessland et al determined a dopaminergic neuron-specific role of SATB1 in modulating Cdkn1a/p21 expression and downstream senescence phenotypes including karyomegaly, mitochondrial dysfunction, production of SASP, lysosomal dysfunction and presence of SA β-gal and lipofuscin [ 56 ].…”

Section: Neuronsmentioning

confidence: 99%

“…While many of these processes including those addressed above are thought to contribute to neuronal degeneration, some are also hypothesized to reflect survival-promoting mechanisms such as senescence. More recent studies focused on neuronal senescence in PD have revealed that overexpression of mutant p53, p21, or mutant Leucine-rich repeat kinase 2 (LRRK2) increased SA β-gal, and αSyn protein expression and fibril accumulation in vitro [ 77 ]. Transgenic mice expressing the same mutant LRRK2 G2019S displayed elevated oligomeric αSyn, β-galactosidase and p21 expression.…”

Section: Neuronsmentioning

confidence: 99%

“…Transgenic mice expressing the same mutant LRRK2 G2019S displayed elevated oligomeric αSyn, β-galactosidase and p21 expression. The increase in αSyn was due to impaired degradation, not increased transcription [ 77 ]. The results suggest that the LRRK2 G2019S mutation may activate the p53-p21 senescence pathway, which is upstream of α-synuclein accumulation.…”

Section: Neuronsmentioning

confidence: 99%

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The Cellular Senescence Stress Response in Post-Mitotic Brain Cells: Cell Survival at the Expense of Tissue Degeneration

Sah

Krishnamurthy

Ahmidouch

et al. 2021

Life

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In 1960, Rita Levi-Montalcini and Barbara Booker made an observation that transformed neuroscience: as neurons mature, they become apoptosis resistant. The following year Leonard Hayflick and Paul Moorhead described a stable replicative arrest of cells in vitro, termed “senescence”. For nearly 60 years, the cell biology fields of neuroscience and senescence ran in parallel, each separately defining phenotypes and uncovering molecular mediators to explain the 1960s observations of their founding mothers and fathers, respectively. During this time neuroscientists have consistently observed the remarkable ability of neurons to survive. Despite residing in environments of chronic inflammation and degeneration, as occurs in numerous neurodegenerative diseases, often times the neurons with highest levels of pathology resist death. Similarly, cellular senescence (hereon referred to simply as “senescence”) now is recognized as a complex stress response that culminates with a change in cell fate. Instead of reacting to cellular/DNA damage by proliferation or apoptosis, senescent cells survive in a stable cell cycle arrest. Senescent cells simultaneously contribute to chronic tissue degeneration by secreting deleterious molecules that negatively impact surrounding cells. These fields have finally collided. Neuroscientists have begun applying concepts of senescence to the brain, including post-mitotic cells. This initially presented conceptual challenges to senescence cell biologists. Nonetheless, efforts to understand senescence in the context of brain aging and neurodegenerative disease and injury emerged and are advancing the field. The present review uses pre-defined criteria to evaluate evidence for post-mitotic brain cell senescence. A closer interaction between neuro and senescent cell biologists has potential to advance both disciplines and explain fundamental questions that have plagued their fields for decades.

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“…The generation of αSyn brils was described in our previous report (19). We transfected cells with 0.15 µg GFP or 1.0 µg GFP-NCL using LipoD293 for 24 h following the 6 h pre-treatment of 700 nM αSyn brils.…”

Section: Uptake Of αSyn Brilsmentioning

confidence: 99%

Expression of transduced Nucleolin promotes the clearance of accumulated alpha-synuclein

Nam

Jeong

et al. 2020

Preprint

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Background Alpha-synuclein (αSyn) is a major component of Lewy bodies, which are known to be a pathogenic marker of Parkinson’s disease (PD). The accumulation of αSyn is caused by dysfunctions in protein degradation machinery. The reinforcement of αSyn degradation is a potential therapeutic target of PD since accumulated αSyn is responsible for the pathogenesis of PD. Nucleolin (NCL) is essential for forming nucleolar structure. The function of NCL is correlated with oxidative stress-mediated cell death. A previous study demonstrated that NCL was reduced in PD brains, and overexpression of NCL alleviated rotenone-induced neural toxic effects. Knockdown of NCL had the opposite effect. These results suggest that the malfunctioning of NCL would exacerbate PD pathology. Thus, we hypothesized that the introduction of ectopic NCL could rescue the α-synucleinopathy in PD. Methods We tested whether ectopic expression of NCL facilitates the clearance of αSyn. The Ectopic expression of NCL was accomplished by the transfection of GFP or GFP-NCL in mouse embryonic fibroblasts (MEF) or transduction of green fluorescent protein (GFP) or GFP-NCL using lentivirus in rat primary cortical neuron. We also investigated whether the expression of GFP or GFP-NCL in mouse substantia nigra alleviates the PD pathology derived by αSyn aggregates. Results The expression of NCL enhanced the clearance of αSyn accumulation or aggregates in MEF and rat primary cortical neurons. The activity of autophagy-lysosome pathway was enhanced by NCL expression. The transduction of NCL in the substantia nigra, which was co-injected with αSyn fibrils, rescued PD manifestations. Conclusions The elevation of NCL levels may reflect a therapeutic strategy for α-synucleinopathy in PD.

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Upregulation of the p53-p21 pathway by G2019S LRRK2 contributes to the cellular senescence and accumulation of α-synuclein

Cited by 28 publications

References 38 publications

Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells

Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells

The Cellular Senescence Stress Response in Post-Mitotic Brain Cells: Cell Survival at the Expense of Tissue Degeneration

Expression of transduced Nucleolin promotes the clearance of accumulated alpha-synuclein

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