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14-3-3 Proteins regulate mutant LRRK...

Lavalley, Nicholas J.

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

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening./
作者:	Lavalley, Nicholas J.
面頁冊數:	193 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-09(E), Section: B.
Contained By:	Dissertation Abstracts International77-09B(E).
標題:	Neurosciences. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10105851
ISBN:	9781339693026

14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening.
Lavalley, Nicholas J.

14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening. - 193 p.

Source: Dissertation Abstracts International, Volume: 77-09(E), Section: B.

Thesis (Ph.D.)--The University of Alabama at Birmingham, 2016.

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&thgr; overexpression, neurite length of primary neurons from BAC transgenic G2019S-LRRK2 mice returned back to wildtype levels. Similarly, 14-3-3&thgr; 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&thgr; further reduced neurite length in G2019S-LRRK2 cultures. Since G2019S-LRRK2 toxicity is likely mediated through increased kinase activity, we examined 14-3-3&thgr;'s effects on LRRK2 kinase activity. 14-3-3&thgr; overexpression reduced the kinase activity of G2019S-LRRK2, while difopein promoted the kinase activity of G2019S-LRRK2. The ability of 14-3-3s to reduce LRRK2 kinase activity required direct binding of 14-3-3&thgr; 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&thgr; can regulate LRRK2 and reduce the toxicity of mutant LRRK2 through a reduction of kinase activity.

ISBN: 9781339693026Subjects--Topical Terms:

588700
Neurosciences.

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