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- Title
G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons.
- Authors
Volpicelli-Daley, Laura A.; Abdelmotilib, Hisham; Zhiyong Liu; Stoyka, Lindsay; Lima Daher, Joõo Paulo; Milnerwood, Austen J.; Unni, Vivek K.; Hirst, Warren D.; Zhenyu Yue; Zhao, Hien T.; Fraser, Kyle; Kennedy, Richard E.; West, Andrew B.
- Abstract
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 of WT-LRRK2 not 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 a-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 a-synuclein that is more susceptible to forming inclusions.
- Subjects
PARKINSON'S disease; SYNUCLEINS; CARRIER proteins; NERVE tissue proteins; NEURONS; LEWY body dementia
- Publication
Journal of Neuroscience, 2016, Vol 38, Issue 28, p7415
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3642-15.2016