Details

Autor(en) / Beteiligte

• Volpicelli-Daley, L. A.
• Abdelmotilib, H.
• Liu, Z.
• Stoyka, L.
• Daher, J. P. L.
• Milnerwood, A. J.
• Unni, V. K.
• Hirst, W. D.
• Yue, Z.
• Zhao, H. T.
• Fraser, K.
• Kennedy, R. E.
• West, A. B.

Titel

G2019S-LRRK2 Expression Augments  -Synuclein Sequestration into Inclusions in Neurons

Ist Teil von

• The Journal of neuroscience, 2016-07, Vol.36 (28), p.7415-7427

Erscheinungsjahr

2016

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Pathologic inclusions define [alpha]-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 [alpha]-synuclein, LRRK2, and the formation of [alpha]-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 [alpha]-synuclein into inclusions in response to [alpha]-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 [alpha]-synuclein. Knockdown of total [alpha]-synuclein with potent antisense oligonucleotides substantially reduces inclusion formation in G2019S-LRRK2-expressing neurons, suggesting that LRRK2 influences [alpha]-synuclein inclusion formation by altering [alpha]-synuclein levels. These findings support the hypothesis that G2019S-LRRK2 may increase the progression of pathological [alpha]-synuclein inclusions after the initial formation of [alpha]-synuclein pathology by increasing a pool of [alpha]-synuclein that is more susceptible to forming inclusions.