ArticleJournal of neural transmission (Vienna, Austria : 1996)2015
G2019S LRRK2 and aging confer susceptibility to proteasome inhibitor-induced neurotoxicity in nigrostriatal dopaminergic system.
Article in Journal of neural transmission (Vienna, Austria : 1996), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 17 citations in OpenAlex.
- Nurr1 deficiency impairs autophagy-lysosomal function through GBA-dependent transcriptional regulation in Parkinson's disease pathogenesis.Frontiers in aging neuroscience · 2025Article
- LRRK2Journal of cachexia, sarcopenia and muscle · 2024Article
- Altered Motor Performance, Sleep EEG, and Parkinson's Disease Pathology Induced by Chronic Sleep Deprivation in Lrrk2Neuroscience bulletin · 2022Article
- Age-related LRRK2 G2019S Mutation Impacts Microglial Dopaminergic Fiber Refinement and Synaptic Pruning Involved in Abnormal Behaviors.Journal of molecular neuroscience : MN · 2022Article
- The essential role of transcription factor Pitx3 in preventing mesodiencephalic dopaminergic neurodegeneration and maintaining neuronal subtype identities during aging.Cell death & disease · 2021Article
- Essential role for autophagy protein VMP1 in maintaining neuronal homeostasis and preventing axonal degeneration.Cell death & disease · 2021Article
- Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway.Frontiers in cellular neuroscience · 2021Article
- Nurr1Glia · 2020Article
- G2019S Variation in LRRK2: An Ideal Model for the Study of Parkinson's Disease?Frontiers in human neuroscience · 2019Review
- Characterization of Parkinson's disease-related pathogenic TMEM230 mutants.Animal cells and systems · 2018Article
- The Proteasome Inhibition Model of Parkinson's Disease.Journal of Parkinson's disease · 2017Review
- The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration.Frontiers in cellular neuroscience · 2017Article
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Authors and funding
3 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
The leucine-rich repeat kinase 2 (LRRK2) mutation G2019S is one of the most common genetic causes in Parkinson's disease (PD). The penetrance of G2019S LRRK2 is incomplete and is age-dependent, therefore, it has been speculated that environmental toxins and aging could contribute to G2019S LRRK2-related PD pathogenesis. To prove this speculation, we performed a longitudinal investigation in mice bearing G2019S LRRK2 mutation. BAC G2019S LRRK2 transgenic (Tg) mice and their wildtype (Wt) littermates were treated with lactacystin, a specific proteasome inhibitor. The susceptibilities of mice to lactacystin-induced nigrostriatal dopaminergic (DAergic) degeneration were evaluated, at 5 and 12 months of age. We found that lactacystin treatment caused a greater decline of striatal DA content in the Tg mice at either 5 or 12 months of age than their age-matched Wt littermates. Moreover, the lactacystin-treated Tg or Wt mice at 12 months of age lose much more nigral tyrosine hydroxylase (TH)-positive neurons than the mice at 5 months of age, indicating an age-associated DAergic neurotoxicity. Additionally, stereotactic injection of lactacystin induced a dramatic increase of activated microglia in substantia nigra of mice at 12 months of age, compared with mice at 5 months of age. In summary, our study suggests that expression of the G2019S mutation in the mouse LRRK2 gene confers an age-associated high susceptibility to proteasome inhibition-induced nigrostriatal DAergic degeneration.
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