ArticleThe EMBO journal2020
LRRK2 regulates endoplasmic reticulum-mitochondrial tethering through the PERK-mediated ubiquitination pathway.
Article in The EMBO journal, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 74 papers, 3 of them syntheses that pooled it.
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Who cites it
74 citing papers in PubMed, 3 syntheses or guidelines pooled it, 100 citations in OpenAlex.
- The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases.Molecular neurobiology · 2023Pooled it
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites.Frontiers in neuroscience · 2022Pooled it
- Mitochondria-associated endoplasmic reticulum membranes and calcium ion exchange: A novel direction for aging and neurodegenerative diseases.Neural regeneration research · 2026Article
- Ubiquitin and ubiquitin-like modifications in the endoplasmic reticulum stress response.The FEBS journal · 2026Review
- Discovery of potent and selective LRRK2 inhibitors with preserved activity against the G2019S mutant via multi-stage virtual screening.Journal of computer-aided molecular design · 2026Article
- The vicious cycle: unraveling the interplay between α-synuclein, mitochondrial dysfunction, and neuroinflammation in Parkinson's disease.Journal of neurology · 2026Review
- LRRK2 I1371V Mutation Drives Astrocytic Glucose Metabolism Failure and Induces Integrated ER-Mitochondria-Lysosome Dysfunction in Parkinson's Disease.International journal of molecular sciences · 2026Article
- Role of LRRK2 in physiological activities, diseases, and therapy.Chinese medical journal · 2026Review
- The role of ER-associated degradation and ER-phagy in health and disease.Signal transduction and targeted therapy · 2026Review
- Mitochondria-ER contact sites in neurological disorders.Animal cells and systems · 2026Review
- Parkin Deficiency Impairs ER-Mitochondria Associations and calcium homeostasis via IP3R-Grp75-VDAC1 Complex.International journal of biological sciences · 2026Article
- Ubiquitination in the Nervous System: From Molecular Mechanisms to Disease Implications.Molecular neurobiology · 2025Review
- March5-mediated Trim28 degradation preserves islet β-cell function in mice.Nature communications · 2025Article
- Role of LRRK2 in axonal transport and Parkinson's disease.The Biochemical journal · 2025Review
- Mitochondria-Associated Membranes: A Key Point of Neurodegenerative Diseases.CNS neuroscience & therapeutics · 2025Review
- The Multifaceted Role of LRRK2 in Parkinson's Disease.Brain sciences · 2025Review
- Transcriptome signatures of human neural stem cells derived from LRRK2 gene therapeutic cells.Scientific reports · 2025Article
- Parkinson's Disease: The Neurodegenerative Enigma Under the "Undercurrent" of Endoplasmic Reticulum Stress.International journal of molecular sciences · 2025Review
- Article
14 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson's disease (PD). Impaired mitochondrial function is suspected to play a major role in PD. Nonetheless, the underlying mechanism by which impaired LRRK2 activity contributes to PD pathology remains unclear. Here, we identified the role of LRRK2 in endoplasmic reticulum (ER)-mitochondrial tethering, which is essential for mitochondrial bioenergetics. LRRK2 regulated the activities of E3 ubiquitin ligases MARCH5, MULAN, and Parkin via kinase-dependent protein-protein interactions. Kinase-active LRRK2(G2019S) dissociated from these ligases, leading to their PERK-mediated phosphorylation and activation, thereby increasing ubiquitin-mediated degradation of ER-mitochondrial tethering proteins. By contrast, kinase-dead LRRK2(D1994A)-bound ligases blocked PERK-mediated phosphorylation and activation of E3 ligases, thereby increasing the levels of ER-mitochondrial tethering proteins. Thus, the role of LRRK2 in the ER-mitochondrial interaction represents an important control point for cell fate and pathogenesis in PD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.