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Biochim Biophys Acta. 2015 Jan;1852(1):12-21. doi: 10.1016/j.bbadis.2014.11.009. Epub 2014 Nov 15.

Threonine 56 phosphorylation of Bcl-2 is required for LRRK2 G2019S-induced mitochondrial depolarization and autophagy.

Su YC#1, Guo X#1, Qi X1,2.

Author information

1
Department of Physiology and Biophysics Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
2
Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
#
Contributed equally

Abstract

The G2019S leucine-rich repeat kinase 2 (LRRK2) mutation is the most common cause of genetic Parkinson's disease (PD). However, the molecular mechanism underlying LRRK2 G2019S-induced cellular pathology is poorly understood. Here, we demonstrated that LRRK2 G2019S bound to and phosphorylated Bcl-2, a mitochondrial anti-apoptotic protein, at Threonine 56. Either stable expression of Bcl-2 or transient expression of a Bcl-2 phosphor mutant (Bcl-2(T56A)) abolished LRRK2 G2019S-induced mitochondrial depolarization and autophagy. Together, our findings reveal a previously unidentified target of LRRK2 G2019S, showing that Bcl-2 serves as a point of crosstalk between LRRK2 G2019S-mediated mitochondrial disorder and dysregulation of autophagy.

KEYWORDS:

Bcl-2; LRRK2 G2019S; Mitochondrial depolarization; Mitophagy; Phosphorylation

PMID:
25446991
PMCID:
PMC4268371
DOI:
10.1016/j.bbadis.2014.11.009
[Indexed for MEDLINE]
Free PMC Article

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