title: Threonine 56 phosphorylation of Bcl-2 is required for LRRK2 G2019S-induced mitochondrial depolarization and autophagy.
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.
authors.affiliation: Department of Physiology and Biophysics Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Su
authors.affiliation: Department of Physiology and Biophysics Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Physiology and Biophysics Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.|Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
mesh_terms: D001343:Autophagy; D001665:Binding Sites; D006367:HeLa Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008928:Mitochondria / Q000502:physiology*; D063306:Mitophagy; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D013912:Threonine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: Bcl-2; LRRK2 G2019S; Mitochondrial depolarization; Mitophagy; Phosphorylation