ArticleCell cycle (Georgetown, Tex.)2019
Upregulation of the p53-p21 pathway by G2019S LRRK2 contributes to the cellular senescence and accumulation of α-synuclein.
Article in Cell cycle (Georgetown, Tex.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 36 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Rethinking Senescence Hallmarks in the Brain: Lessons From Peripheral Tissues and Challenges in Defining Neuronal Senescence.Aging cell · 2026Review
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- A hypothesis explaining Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies overlap.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Review
- The Multifaceted Role of LRRK2 in Parkinson's Disease.Brain sciences · 2025Review
- Aging, cellular senescence and Parkinson's disease.Journal of Parkinson's disease · 2025Review
- Nuclear alpha-synuclein accelerates cell senescence and neurodegeneration.Immunity & ageing : I & A · 2024Article
- An Antibody-directed and Immune Response Modifier-augmented Photothermal Therapy Strategy Relieves Aging via Rapid Immune Clearance of Senescent Cells.Aging and disease · 2024Article
- Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies.bioRxiv : the preprint server for biology · 2024Article
- Repression of YEATS2 induces cellular senescence in hepatocellular carcinoma and inhibits tumor growth.Cell cycle (Georgetown, Tex.) · 2024Article
- The Common Denominators of Parkinson's Disease Pathogenesis and Methamphetamine Abuse.Current neuropharmacology · 2024Review
- Ultra-small polydopamine nanomedicine-enabled antioxidation against senescence.Materials today. Bio · 2023Article
- Spermidine Retarded the Senescence of Multipotent Mesenchymal Stromal CellsStem cells international · 2023Article
- Senescence: A DNA damage response and its role in aging and Neurodegenerative Diseases.Frontiers in aging · 2023Review
- Human Induced Pluripotent Stem Cell Phenotyping and Preclinical Modeling of Familial Parkinson's Disease.Genes · 2022Review
- Photoinduced elimination of senescent microglia cellsChemical science · 2022Article
- Article
- Association of p53 with Neurodegeneration in Parkinson's Disease.Parkinson's disease · 2022Review
- The protective effects of Ramelteon against 6-OHDA-induced cellular senescence in human SH-SY5Y neuronal cells.Brain and behavior · 2021Article
- The Cellular Senescence Stress Response in Post-Mitotic Brain Cells: Cell Survival at the Expense of Tissue Degeneration.Life (Basel, Switzerland) · 2021Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (LB) in neurons. α-Synuclein (αSyn) is a major component of LB and promote the PD pathogenesis via its accumulation by the impaired proteasomal or autophagic clearance. Numerous studies have revealed that the reduction of proteasome activity and autophagy is accelerated by cellular senescence. Leucine-rich repeat kinase 2 (LRRK2) contributes to PD progression and its most prevalent mutation, G2019S LRRK2, increases its activity. Our previous report has shown that the G2019S LRRK2 mutant promoted p53-induced p21 expression and neuronal cytotoxicity. The p53-p21 pathway plays a role in cellular senescence. We hypothesized that the loss of dopaminergic neurons by the stimulated p53-p21 pathway via the G2019S LRRK2 mutation might be associated with cellular senescence, thereby promoting the accumulation of αSyn. We confirmed that the ectopic expression of the phosphomimetic p53 mutant, p21, or G2019 in differentiated SH-SY5Y cells increased the following: 1) the expression of β-galactosidase, a marker of cellular senescence, and the activity of senescence-associated β-galactosidase, 2) endogenous αSyn protein level, but not its mRNA level, and 3) αSyn fibril accumulation in dSH-SY5Y via low proteasome and cathepsin D activities. Elevated oligomeric αSyn and the increase in β-galactosidase with induced p21 were observed in brain lysates of G2019S transgenic mice. Our results suggest that cellular senescence is promoted via the p53-p21 pathway due to the G2019S LRRK2 mutation. Eventually, decreased protein degradation by G2019S-mediated senescence could accelerate αSyn aggregate formation.
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