LRRK2 regulates synaptic vesicle endocytosis.
The leucine-rich repeat kinase 2 (LRRK2) has been identified as the defective gene at the PARK8 locus causing the autosomal dominant form of Parkinson's disease (PD). Although several LRRK2 mutations were found in familial as well as sporadic PD patients, its physiological functions are not clearly defined. In this study, using yeast two-hybrid screening, we report the identification of Rab5b as an LRRK2-interacting protein. Indeed, our GST pull down and co-immunoprecipitation assays showed that it specifically interacts with LRRK2. In addition, subcellular fractionation and immunocytochemical analyses confirmed that a fraction of both proteins co-localize in synaptic vesicles. Interestingly, we found that alteration of LRRK2 expression by either overexpression or knockdown of endogenous LRRK2 in primary neuronal cells significantly impairs synaptic vesicle endocytosis. Furthermore, this endocytosis defect was rescued by co-expression of functional Rab5b protein, but not by its inactive form. Taken together, we propose that LRRK2, in conjunction with its interaction with Rab5b, plays an important role in synaptic function by modulating the endocytosis of synaptic vesicles.
Shin
Narae
N
Department of Life Science, GIST, Buk-gu, Gwangju, South Korea.
Jeong
Hyerhan
H
Kwon
Jungsun
J
Heo
Hye Young
HY
Kwon
Jung June
JJ
Yun
Hye Jin
HJ
Kim
Cy-Hyun
CH
Han
Baek Soo
BS
Tong
Youren
Y
Shen
Jie
J
Hatano
Taku
T
Hattori
Nobutaka
N
Kim
Kwang-Soo
KS
Chang
Sunghoe
S
Seol
Wongi
W
D000818:Animals; D002460:Cell Line; D004705:Endocytosis / Q000502:physiology*; D005089:Exocytosis / Q000502:physiology; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013569:Synapses / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D020696:rab5 GTP-Binding Proteins