ArticleCell death & disease2014
The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling.
Article in Cell death & disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 99 citations in OpenAlex.
- Small-molecule autophagy modulators: Mechanisms, therapeutic potential, and development challenges in pathological settings.Fundamental research · 2026Review
- Role of LRRK2 in physiological activities, diseases, and therapy.Chinese medical journal · 2026Review
- APurinergic signalling · 2026Article
- Recent advances in targeting LRRK2 for Parkinson's disease treatment.Journal of translational medicine · 2025Review
- LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.The Biochemical journal · 2025Review
- The Multifaceted Role of LRRK2 in Parkinson's Disease.Brain sciences · 2025Review
- Genetic mutations in kinases: a comprehensive review on marketed inhibitors and unexplored targets in Parkinson's disease.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Review
- Unraveling the Ties: Type 2 Diabetes and Parkinson's Disease - A Nano-Based Targeted Drug Delivery Approach.Current diabetes reviews · 2025Review
- METTL3-mediated m6A modification regulates D-galactose-induced skin fibroblast senescence through miR-208a-5p.Frontiers in immunology · 2025Article
- Article
- The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function and protects against alpha-synuclein neuropathology.NPJ Parkinson's disease · 2023Article
- Mitochondria-Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations.International journal of molecular sciences · 2023Review
- Characterization of Lipopolysaccharide Effects on LRRK2 Signaling in RAW Macrophages.International journal of molecular sciences · 2023Article
- Association between Parkinson's Disease and Diabetes Mellitus: From Epidemiology, Pathophysiology and Prevention to Treatment.Aging and disease · 2022Article
- The parkinsonian LRRK2 R1441G mutation shows macroautophagy-mitophagy dysregulation concomitant with endoplasmic reticulum stress.Cell biology and toxicology · 2022Article
- LRRK2 regulates actin assembly for spindle migration and mitochondrial function in mouse oocyte meiosis.Journal of molecular cell biology · 2022Article
- Downregulation of lncRNA MEG3 is involved in Parkinson's disease.Metabolic brain disease · 2021Article
- Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease.Acta pharmaceutica Sinica. B · 2021Review
- Ceramide Metabolism and Parkinson's Disease-Therapeutic Targets.Biomolecules · 2021Review
- Genetic Imaging of Neuroinflammation in Parkinson's Disease: Recent Advancements.Frontiers in cell and developmental biology · 2021Review
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been associated with Parkinson's disease, and its inhibition opens potential new therapeutic options. Among the drug inhibitors of both wild-type and mutant LRRK2 forms is the 2-arylmethyloxy-5-subtitutent-N-arylbenzamide GSK257815A. Using the well-established dopaminergic cell culture model SH-SY5Y, we have investigated the effects of GSK2578215A on crucial neurodegenerative features such as mitochondrial dynamics and autophagy. GSK2578215A induces mitochondrial fragmentation of an early step preceding autophagy. This increase in autophagosome results from inhibition of fusion rather than increases in synthesis. The observed effects were shared with LRRK2-IN-1, a well-described, structurally distinct kinase inhibitor compound or when knocking down LRRK2 expression using siRNA. Studies using the drug mitochondrial division inhibitor 1 indicated that translocation of the dynamin-related protein-1 has a relevant role in this process. In addition, autophagic inhibitors revealed the participation of autophagy as a cytoprotective response by removing damaged mitochondria. GSK2578215A induced oxidative stress as evidenced by the accumulation of 4-hydroxy-2-nonenal in SH-SY5Y cells. The mitochondrial-targeted reactive oxygen species scavenger MitoQ positioned these species as second messengers between mitochondrial morphologic alterations and autophagy. Altogether, our results demonstrated the relevance of LRRK2 in mitochondrial-activated pathways mediating in autophagy and cell fate, crucial features in neurodegenerative diseases.
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