LRRK2 and the “LRRKtosome” at the Crossroads of Programmed Cell Death: Clues from RIP Kinase Relatives

Abstract

Since its cloning and identification in 2004, considerable gains have been made in the understanding of the basic functionality of leucine-rich repeat kinase 2 (LRRK2), including its kinase and GTPase activities, its protein interactors and subcellular localization, and its expression in the CNS and peripheral tissues. However, the mechanism(s) by which expression of mutant forms of LRRK2 lead to the death of dopaminergic neurons of the ventral midbrain remains largely uncharacterized. Because of its complex domain structure, LRRK2 exhibits similarities with multiple protein families including ROCO proteins, as well as the RIP kinases. Cellular models in which mutant LRRK2 is overexpressed in neuronal-like cell lines or in primary neurons have found evidence of apoptotic cell death involving components of the extrinsic as well as intrinsic death pathways. However, since the expression of LRRK2 is comparatively quite low in ventral midbrain dopaminergic neurons, the possibility exists that non-cell autonomous signaling also contributes to the loss of these neurons. In this chapter, we will discuss the different neuronal death pathways that may be activated by mutant forms of LRRK2, guided in part by the behavior of other members of the RIP kinase protein family.

LRRK2 at the Interface Between Peripheral and Central Immune Function in Parkinson’s

“…LRRK2 is expressed in both innate and adaptive immune cells and this expression is tightly regulated by immune stimulation. LRRK2 is a member of the receptor interacting protein (RIP) kinase family, which are a group of proteins that detect and respond to cellular stress by regulating cell death and activation of the immune system (Rideout and Re, 2017), highlighting a potential role of LRRK2 in immune system regulation. This is supported by reports biochemically linking LRRK2 to the pathways regulating inflammation, autophagy and phagocytosis in immune cells (Wallings and Tansey, 2019).…”

Mitochondrial dysfunction promotes alternative gasdermin D-mediated inflammatory cell death and susceptibility to infection

“…Despite having connected a number of LRRK2-dependent mitochondrial defects to the GSDMD-dependent necroptotic cell death we describe here, the precise mechanistic contribution of LRRK2, and LRRK2 kinase activity to the death of Lrrk2 G2019S macrophages, is still not entirely clear. One intriguing possibility is that the ability of Lrrk2 G2019S to push cells towards RIPK3-dependent necroptotic cell death is driven in part by LRRK2 itself being a RIP (receptor interacting protein) kinase family member (LRRK2 is sometimes annotated as RIPK7) 150 . A recent siRNA screen identified LRRK2 as a positive regulator of RIPK1-dependent apoptosis in a photoreceptor cell line and in MEFs 151 and there is evidence that LRRK2 can co-immunoprecipitate with RIPK1 and FADD in HEK293T cells 152 .…”

Rola białka RIPK4 w fizjologii naskórka.

“…W ich strukturze można wyróżnić domenę Ras złożonych białek/C-koniec Roc (Roc/COR), powtórzenia ankirynowe oraz motyw WD40 (RIPK7). RIPK7 zostało rozpoznane jako istotne białko w patogenezie chorób neurodegeneracyjnych, przede wszystkim w chorobie Parkinsona [8].…”