title: G2019S LRRK2 and aging confer susceptibility to proteasome inhibitor-induced neurotoxicity in nigrostriatal dopaminergic system.
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.
authors.affiliation: Institute of Neurology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Center for Translational Research on Neurological Diseases, 1st Affiliated Hospital of Dalian Medical University, Dalian, 116011, Liaoning, China.
authors.forename: Suosuo
authors.initials: S
authors.lastname: Yang
authors.affiliation: Institute of Neurology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. wdle@sibs.ac.cn.|Center for Translational Research on Neurological Diseases, 1st Affiliated Hospital of Dalian Medical University, Dalian, 116011, Liaoning, China. wdle@sibs.ac.cn.
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000633:toxicity; D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology*; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology / Q000502:physiology; D020022:Genetic Predisposition to Disease; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000473:pathology / Q000503:physiopathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015853:Cysteine Proteinase Inhibitors; C067713:lactacystin; D014446:Tyrosine 3-Monooxygenase; D017346:Protein Serine-Threonine Kinases; D000111:Acetylcysteine
keywords: Aging; G2019S mutation; Lactacystin; Leucine-rich repeat kinase 2; Parkinson’s disease