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

• LRRK2 G2019S bound to and phosphorylated Bcl-2 at Thr56.
• Phosphorylation of Bcl-2 by LRRK2 G2019S augmented autophagic process.
• Bcl-2 phosphor mutant, Bcl-2T56A, corrected autophagic damage and neuronal injury induced by LRRK2 G2019S.

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-2T56A) 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.