I(2020)T leucine-rich repeat kinase 2, the causative mutant molecule of familial Parkinson's disease, has a higher intracellular degradation rate than the wild-type molecule.
Leucine-rich repeat kinase 2 (LRRK2) has been identified as the causal gene for autosomal dominant familial Parkinson's disease (PD), although the mechanism of neurodegeneration involving the mutant LRRK2 molecules remains unknown. In the present study, we found that the protein level of transfected I(2020)T mutant LRRK2 was significantly lower than that of wild-type and G(2019)S mutant LRRK2, although the intracellular localization of the I(2020)T and wild-type molecules did not differ. Pulse-chase experiments proved that the I(2020)T LRRK2 molecule has a higher degradation rate than wild-type or G(2019)S LRRK2. Upon addition of proteasome and lysosome inhibitors, the protein level of I(2020)T mutant LRRK2 reached that of the wild-type. These results indicate that I(2020)T mutant LRRK2 is more susceptible to post-translational degradation than the wild-type molecule. Our results indicate a novel molecular feature characteristic to I(2020)T LRRK2, and provide a new insight into the mechanism of neurodegeneration caused by LRRK2.
Ohta
Etsuro
E
Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa 228-8555, Japan.
Katayama
Yuri
Y
Kawakami
Fumitaka
F
Yamamoto
Matsuri
M
Tajima
Kana
K
Maekawa
Tatsunori
T
Iida
Naoyuki
N
Hattori
Seisuke
S
Obata
Fumiya
F
D019943:Amino Acid Substitution; D002460:Cell Line; D006801:Humans; D007532:Isoleucine / Q000235:genetics / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D007532:Isoleucine; D013912:Threonine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases