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

Academic Article


  • 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.
  • Digital Object Identifier (doi)

    Author List

  • Volpicelli-Daley LA; Abdelmotilib H; Liu Z; Stoyka L; Daher JPL; Milnerwood AJ; Unni VK; Hirst WD; Yue Z; Zhao HT
  • Start Page

  • 7415
  • End Page

  • 7427
  • Volume

  • 36
  • Issue

  • 28