| First Author | Lavalley NJ | Year | 2016 |
| Journal | Hum Mol Genet | Volume | 25 |
| Issue | 1 | Pages | 109-22 |
| PubMed ID | 26546614 | Mgi Jnum | J:227621 |
| Mgi Id | MGI:5702334 | Doi | 10.1093/hmg/ddv453 |
| Citation | Lavalley NJ, et al. (2016) 14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening. Hum Mol Genet 25(1):109-22 |
| abstractText | Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of inherited Parkinson's disease (PD), and LRRK2 is a risk factor for idiopathic PD. How LRRK2 function is regulated is not well understood. Recently, the highly conserved 14-3-3 proteins, which play a key role in many cellular functions including cell death, have been shown to interact with LRRK2. In this study, we investigated whether 14-3-3s can regulate mutant LRRK2-induced neurite shortening and kinase activity. In the presence of 14-3-3theta overexpression, neurite length of primary neurons from BAC transgenic G2019S-LRRK2 mice returned back to wild-type levels. Similarly, 14-3-3theta overexpression reversed neurite shortening in neuronal cultures from BAC transgenic R1441G-LRRK2 mice. Conversely, inhibition of 14-3-3s by the pan-14-3-3 inhibitor difopein or dominant-negative 14-3-3theta further reduced neurite length in G2019S-LRRK2 cultures. Since G2019S-LRRK2 toxicity is likely mediated through increased kinase activity, we examined 14-3-3theta's effects on LRRK2 kinase activity. 14-3-3theta overexpression reduced the kinase activity of G2019S-LRRK2, while difopein promoted the kinase activity of G2019S-LRRK2. The ability of 14-3-3theta to reduce LRRK2 kinase activity required direct binding of 14-3-3theta with LRRK2. The potentiation of neurite shortening by difopein in G2019S-LRRK2 neurons was reversed by LRRK2 kinase inhibitors. Taken together, we conclude that 14-3-3theta can regulate LRRK2 and reduce the toxicity of mutant LRRK2 through a reduction of kinase activity. |
