| First Author | Volpicelli-Daley LA | Year | 2016 |
| Journal | J Neurosci | Volume | 36 |
| Issue | 28 | Pages | 7415-27 |
| PubMed ID | 27413152 | Mgi Jnum | J:311063 |
| Mgi Id | MGI:6765126 | Doi | 10.1523/JNEUROSCI.3642-15.2016 |
| Citation | Volpicelli-Daley LA, et al. (2016) G2019S-LRRK2 Expression Augments alpha-Synuclein Sequestration into Inclusions in Neurons. J Neurosci 36(28):7415-27 |
| abstractText | UNLABELLED: 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. SIGNIFICANCE STATEMENT: alpha-Synuclein inclusions are found in the brains of patients with many different neurodegenerative diseases. Point mutation, duplication, or triplication of the alpha-synuclein gene can all cause Parkinson's disease (PD). The G2019S mutation in LRRK2 is the most common known genetic cause of PD. The interaction between G2019S-LRRK2 and alpha-synuclein may uncover new mechanisms and targets for neuroprotection. Here, we show that expression of G2019S-LRRK2 increases alpha-synuclein mobility and enhances aggregation of alpha-synuclein in primary cultured neurons and in dopaminergic neurons of the substantia nigra pars compacta, a susceptible brain region in PD. Potent LRRK2 kinase inhibitors, which are being developed for clinical use, block the increased alpha-synuclein aggregation in G2019S-LRRK2-expressing neurons. These results demonstrate that alpha-synuclein inclusion formation in neurons can be blocked and that novel therapeutic compounds targeting this process by inhibiting LRRK2 kinase activity may slow progression of PD-associated pathology. |
