RRC ID 31728
著者 Yao C, Johnson WM, Gao Y, Wang W, Zhang J, Deak M, Alessi DR, Zhu X, Mieyal JJ, Roder H, Wilson-Delfosse AL, Chen SG.
タイトル Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2 toxicity.
ジャーナル Hum Mol Genet
Abstract Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent known cause of late-onset Parkinson's disease (PD). To explore the therapeutic potential of small molecules targeting the LRRK2 kinase domain, we characterized two LRRK2 kinase inhibitors, TTT-3002 and LRRK2-IN1, for their effects against LRRK2 activity in vitro and in Caenorhabditis elegans models of LRRK2-linked neurodegeneration. TTT-3002 and LRRK2-IN1 potently inhibited in vitro kinase activity of LRRK2 wild-type and mutant proteins, attenuated phosphorylation of cellular LRRK2 and rescued neurotoxicity of mutant LRRK2 in transfected cells. To establish whether LRRK2 kinase inhibitors can mitigate pathogenesis caused by different mutations including G2019S and R1441C located within and outside of the LRRK2 kinase domain, respectively, we evaluated effects of TTT-3002 and LRRK2-IN1 against R1441C- and G2019S-induced neurodegeneration in C. elegans models. TTT-3002 and LRRK2-IN1 rescued the behavioral deficit characteristic of dopaminergic impairment in transgenic C. elegans expressing human R1441C- and G2019S-LRRK2. The inhibitors displayed nanomolar to low micromolar rescue potency when administered either pre-symptomatically or post-symptomatically, indicating both prevention and reversal of the dopaminergic deficit. The same treatments also led to long-lasting prevention and rescue of neurodegeneration. In contrast, TTT-3002 and LRRK2-IN1 were ineffective against the neurodegenerative phenotype in transgenic worms carrying the inhibitor-resistant A2016T mutation of LRRK2, suggesting that they elicit neuroprotective effects in vivo by targeting LRRK2 specifically. Our findings indicate that the LRRK2 kinase activity is critical for neurodegeneration caused by R1441C and G2019S mutations, suggesting that kinase inhibition of LRRK2 may represent a promising therapeutic strategy for PD.
巻・号 22(2)
ページ 328-44
公開日 2013-1-15
DOI 10.1093/hmg/dds431
PII dds431
PMID 23065705
PMC PMC3526163
MeSH Animals Animals, Genetically Modified Caenorhabditis elegans / drug effects* Caenorhabditis elegans / metabolism* Cell Line Disease Models, Animal Gene Expression Regulation Humans Inhibitory Concentration 50 Mutation Neurons / cytology Neurons / drug effects* Neurons / metabolism* Neurotoxins / toxicity Parkinson Disease / genetics Parkinson Disease / metabolism Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology* Protein Serine-Threonine Kinases / antagonists & inhibitors* Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism Protein Serine-Threonine Kinases / toxicity*
IF 5.101
引用数 52
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY GENETICS & HEREDITY
リソース情報
線虫 tm1898