LRRK2 regulates endoplasmic reticulum–mitochondrial tethering through the PERK‐mediated ubiquitination pathway

Mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson's disease (PD). Impaired mitochondrial function is suspected to play a major role in PD. Nonetheless, the underlying mechanism by which impaired LRRK2 activity contributes to PD pathology remains unclear. Here, we identified the role of LRRK2 in endoplasmic reticulum (ER)–mitochondrial tethering, which is essential for mitochondrial bioenergetics. LRRK2 regulated the activities of E3 ubiquitin ligases MARCH5, MULAN, and Parkin via kinase‐dependent protein–protein interactions. Kinase‐active LRRK2(G2019S) dissociated from these ligases, leading to their PERK‐mediated phosphorylation and activation, thereby increasing ubiquitin‐mediated degradation of ER–mitochondrial tethering proteins. By contrast, kinase‐dead LRRK2(D1994A)‐bound ligases blocked PERK‐mediated phosphorylation and activation of E3 ligases, thereby increasing the levels of ER–mitochondrial tethering proteins. Thus, the role of LRRK2 in the ER–mitochondrial interaction represents an important control point for cell fate and pathogenesis in PD.