mTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1

Abstract

Leucine rich repeat kinase 2 is a complex enzyme with both kinase and GTPase activities, closely linked to the pathogenesis of several human disorders including Parkinson’s disease, Crohn’s disease, leprosy and cancer. LRRK2 has been implicated in numerous cellular processes; however its physiological function remains unclear. Recent reports suggest that LRRK2 can act to regulate the cellular catabolic process of macroautophagy, although the precise mechanism whereby this occurs has not been identified. To investigate the signalling events through which LRRK2 acts to influence macroautophagy, the mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) and Beclin-1/phosphatidylinositol 3-kinase (PI3K) pathways were evaluated in astrocytic cell models in the presence and absence of LRRK2 kinase inhibitors. Chemical inhibition of LRRK2 kinase activity resulted in the stimulation of macroautophagy in a non-canonical fashion, independent of mTOR and ULK1, but dependent upon the activation of Beclin 1-containing class III PI3-kinase.

LRRK2 at the interface of autophagosomes, endosomes and lysosomes

“…LRRK2 kinase inhibition has also been shown to increase levels of the lipdated autophagosome marker LC3-II and the adaptor protein p62 [58, 59]. Recent findings have shown that this kinase-dependent regulation of LC3 lipidation is mediated through Beclin-1 signaling but independent of mTOR/ULK1 signaling, suggesting non-canonincal regulation of autophagy [60]. …”

Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease

“…In a recent study, Ho and colleagues used several cell models including iPSC‐derived mesDA neurons from G2019S carriers to demonstrate that the mTOR regulator leucyl‐tRNA synthetase (LRS) is phosphorylated by LRRK2 in a genotype‐dependent way, and that G2019S‐associated hyperphosphorylation was linked to impairment of the autophagic system (Ho et al., ). These data suggest that LRRK2 may affect macroautophagy at several levels, including phosphorylation of LRS and Beclin‐1 (Manzoni et al., ).…”

“…LRRK2 is pivotally involved in regulating proteostasis by its effect on (at least) two major proteostatic mechanisms: on the one hand, it regulates macroautophagy by affecting the phosphorylation status of the key autophagy protein Beclin‐1 (Manzoni et al., ) and the mammalian target of rapamycin (mTOR) regulator Leucyl‐tRNA synthetase (LRS) (Ho et al., ). On the other hand, LRRK2 is under normal conditions degraded via both proteasomal and lysosomal pathways.…”

“…LRRK2 is pivotally involved in regulating proteostasis by its effect on (at least) two major proteostatic mechanisms: on the one hand, it regulates macroautophagy by affecting the phosphorylation status of the key autophagy protein Beclin-1 (Manzoni et al, 2016) and the mammalian target of rapamycin F I G U R E 1 Reprogramming approaches in combination with genome editing facilitate disease modeling and drug discovery. Somatic cells (skin fibroblasts, blood cells) from healthy or diseased donors are reprogrammed into induced pluripotent stem cells (iPSCs) via various approaches, including ectopic expression of reprogramming factors, combinations of transcription factors and microRNAs or application of small molecules.…”

Genetic control of autophagy underlies pathogenesis of inflammatory bowel disease

“…In mice, defects in LAP lead to an autoimmune-like response to dying cells and uncontrolled inflammation 18 . Additionally, LRRK2 , a gene associated with Parkinson’s disease, Crohn’s disease, and leprosy has recently been shown to negatively regulate a non-canonical autophagy pathway, suggesting that dysregulation of this pathway may directly influence disease susceptibility 23 .…”