G2019s-LRRK2 expression augments α-synuclein sequestration into inclusions in neurons

Laura A. Volpicelli-Daley, Hisham Abdelmotilib, Zhiyong Liu, Lindsay Stoyka, João Paulo Lima Daher, Austen J. Milnerwood, Vivek Unni, Warren D. Hirst, Zhenyu Yue, Hien T. Zhao, Kyle Fraser, Richard E. Kennedy, Andrew B. West

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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 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.

Original languageEnglish (US)
Pages (from-to)7415-7427
Number of pages13
JournalJournal of Neuroscience
Volume36
Issue number28
DOIs
StatePublished - Jul 13 2016

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Keywords

  • Lewy body
  • Lewy neurite
  • LRRK2
  • Parkinson’s
  • Synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Volpicelli-Daley, L. A., Abdelmotilib, H., Liu, Z., Stoyka, L., Daher, J. P. L., Milnerwood, A. J., Unni, V., Hirst, W. D., Yue, Z., Zhao, H. T., Fraser, K., Kennedy, R. E., & West, A. B. (2016). G2019s-LRRK2 expression augments α-synuclein sequestration into inclusions in neurons. Journal of Neuroscience, 36(28), 7415-7427. https://doi.org/10.1523/JNEUROSCI.3642-15.2016