Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein.
Mutations in alpha-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson's disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although overexpression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T alpha-synuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of alpha-synuclein in A53T mice, which likely resulted from the impairment of microtubule dynamics, Golgi organization, and the ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure and suppressed the aggregation and somatic accumulation of alpha-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings demonstrate that overexpression of LRRK2 enhances alpha-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating alpha-synuclein-induced neurodegeneration.
Lin
Xian
X
Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Parisiadou
Loukia
L
Gu
Xing-Long
XL
Wang
Lizhen
L
Shim
Hoon
H
Sun
Lixin
L
Xie
Chengsong
C
Long
Cai-Xia
CX
Yang
Wan-Jou
WJ
Ding
Jinhui
J
Chen
Zsu Zsu
ZZ
Gallant
Paul E
PE
Tao-Cheng
Jung-Hwa
JH
Rudow
Gay
G
Troncoso
Juan C
JC
Liu
Zhihua
Z
Li
Zheng
Z
Cai
Huaibin
H
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D051844:alpha-Synuclein; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases