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14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening.


ABSTRACT: 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 14-3-3? overexpression, neurite length of primary neurons from BAC transgenic G2019S-LRRK2 mice returned back to wild-type levels. Similarly, 14-3-3? 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 14-3-3? further reduced neurite length in G2019S-LRRK2 cultures. Since G2019S-LRRK2 toxicity is likely mediated through increased kinase activity, we examined 14-3-3?'s effects on LRRK2 kinase activity. 14-3-3? overexpression reduced the kinase activity of G2019S-LRRK2, while difopein promoted the kinase activity of G2019S-LRRK2. The ability of 14-3-3? to reduce LRRK2 kinase activity required direct binding of 14-3-3? with LRRK2. The potentiation of neurite shortening by difopein in G2019S-LRRK2 neurons was reversed by LRRK2 kinase inhibitors. Taken together, we conclude that 14-3-3? can regulate LRRK2 and reduce the toxicity of mutant LRRK2 through a reduction of kinase activity.

SUBMITTER: Lavalley NJ 

PROVIDER: S-EPMC4690493 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening.

Lavalley Nicholas J NJ   Slone Sunny R SR   Ding Huiping H   West Andrew B AB   Yacoubian Talene A TA  

Human molecular genetics 20151105 1


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 activit  ...[more]

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