RRC ID 36177
著者 Imai Y, Kobayashi Y, Inoshita T, Meng H, Arano T, Uemura K, Asano T, Yoshimi K, Zhang CL, Matsumoto G, Ohtsuka T, Kageyama R, Kiyonari H, Shioi G, Nukina N, Hattori N, Takahashi R.
タイトル The Parkinson's Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal Pathway.
ジャーナル PLoS Genet
Abstract Leucine-rich repeat kinase 2 (LRRK2) is a key molecule in the pathogenesis of familial and idiopathic Parkinson's disease (PD). We have identified two novel LRRK2-associated proteins, a HECT-type ubiquitin ligase, HERC2, and an adaptor-like protein with six repeated Neuralized domains, NEURL4. LRRK2 binds to NEURL4 and HERC2 via the LRRK2 Ras of complex proteins (ROC) domain and NEURL4, respectively. HERC2 and NEURL4 link LRRK2 to the cellular vesicle transport pathway and Notch signaling, through which the LRRK2 complex promotes the recycling of the Notch ligand Delta-like 1 (Dll1)/Delta (Dl) through the modulation of endosomal trafficking. This process negatively regulates Notch signaling through cis-inhibition by stabilizing Dll1/Dl, which accelerates neural stem cell differentiation and modulates the function and survival of differentiated dopaminergic neurons. These effects are strengthened by the R1441G ROC domain-mutant of LRRK2. These findings suggest that the alteration of Notch signaling in mature neurons is a component of PD etiology linked to LRRK2.
巻・号 11(9)
ページ e1005503
公開日 2015-9-1
DOI 10.1371/journal.pgen.1005503
PII PGENETICS-D-15-00710
PMID 26355680
PMC PMC4565672
MeSH Animals Carrier Proteins / metabolism Dopamine / metabolism Drosophila Endosomes / metabolism* Guanine Nucleotide Exchange Factors / metabolism HEK293 Cells Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Parkinson Disease / enzymology* Protein Binding Protein Serine-Threonine Kinases / metabolism Protein Serine-Threonine Kinases / physiology* Receptors, Notch / metabolism* Signal Transduction / physiology* Ubiquitin-Protein Ligases
IF 5.175
引用数 23
WOS 分野 GENETICS & HEREDITY
リソース情報
ショウジョウバエ DGRC#105935