TY - JOUR
T1 - G2019s-LRRK2 expression augments α-synuclein sequestration into inclusions in neurons
AU - Volpicelli-Daley, Laura A.
AU - Abdelmotilib, Hisham
AU - Liu, Zhiyong
AU - Stoyka, Lindsay
AU - Daher, João Paulo Lima
AU - Milnerwood, Austen J.
AU - Unni, Vivek K.
AU - Hirst, Warren D.
AU - Yue, Zhenyu
AU - Zhao, Hien T.
AU - Fraser, Kyle
AU - Kennedy, Richard E.
AU - West, Andrew B.
N1 - Publisher Copyright:
© 2016 the authors.
PY - 2016/7/13
Y1 - 2016/7/13
N2 - Pathologic inclusions define α-synucleinopathies that include Parkinson’s disease (PD). The most common genetic cause of PD is the G2019S LRRK2 mutation that upregulates LRRK2 kinase activity. However, the interaction between α -synuclein, LRRK2, and the formation of α -synuclein inclusions remains unclear. Here, we show that G2019S-LRRK2 expression, in both cultured neurons and dopaminergic neurons in the rat substantia nigra pars compact, increases the recruitment of endogenous α -synuclein into inclusions in response to α -synuclein fibril exposure. This results from the expression of mutant G2019S-LRRK2, as overexpression ofWT-LRRK2not only does not increase formation of inclusions but reduces their abundance. In addition, treatment of primary mouse neurons with LRRK2 kinase inhibitors, PF-06447475 and MLi-2, blocks G2019S-LRRK2 effects, suggesting that the G2019S-LRRK2 potentiation of inclusion formation depends on its kinase activity. Overexpression of G2019S-LRRK2 slightly increases, whereas WT-LRRK2 decreases, total levels of α -synuclein. Knockdown of total α -synuclein with potent antisense oligonucleotides substantially reduces inclusion formation in G2019S-LRRK2-expressing neurons, suggesting that LRRK2 influences α -synuclein inclusion formation by altering α -synuclein levels. These findings support the hypothesis that G2019S-LRRK2 may increase the progression of pathological α -synuclein inclusions after the initial formation of α -synuclein pathology by increasing a pool of α -synuclein that is more susceptible to forming inclusions.
AB - Pathologic inclusions define α-synucleinopathies that include Parkinson’s disease (PD). The most common genetic cause of PD is the G2019S LRRK2 mutation that upregulates LRRK2 kinase activity. However, the interaction between α -synuclein, LRRK2, and the formation of α -synuclein inclusions remains unclear. Here, we show that G2019S-LRRK2 expression, in both cultured neurons and dopaminergic neurons in the rat substantia nigra pars compact, increases the recruitment of endogenous α -synuclein into inclusions in response to α -synuclein fibril exposure. This results from the expression of mutant G2019S-LRRK2, as overexpression ofWT-LRRK2not only does not increase formation of inclusions but reduces their abundance. In addition, treatment of primary mouse neurons with LRRK2 kinase inhibitors, PF-06447475 and MLi-2, blocks G2019S-LRRK2 effects, suggesting that the G2019S-LRRK2 potentiation of inclusion formation depends on its kinase activity. Overexpression of G2019S-LRRK2 slightly increases, whereas WT-LRRK2 decreases, total levels of α -synuclein. Knockdown of total α -synuclein with potent antisense oligonucleotides substantially reduces inclusion formation in G2019S-LRRK2-expressing neurons, suggesting that LRRK2 influences α -synuclein inclusion formation by altering α -synuclein levels. These findings support the hypothesis that G2019S-LRRK2 may increase the progression of pathological α -synuclein inclusions after the initial formation of α -synuclein pathology by increasing a pool of α -synuclein that is more susceptible to forming inclusions.
KW - LRRK2
KW - Lewy body
KW - Lewy neurite
KW - Parkinson’s
KW - Synuclein
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UR - http://www.scopus.com/inward/citedby.url?scp=84978841976&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.3642-15.2016
DO - 10.1523/JNEUROSCI.3642-15.2016
M3 - Article
C2 - 27413152
AN - SCOPUS:84978841976
SN - 0270-6474
VL - 36
SP - 7415
EP - 7427
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 28
ER -