srep35106.pdf (1.51 MB)
mTOR independent regulation of macroautophagy by Leucine rich repeat kinase 2 via Beclin-1
journal contributionposted on 2020-08-20, 16:44 authored by Claudia Manzoni, Adamantios Mamais, Dorien A Roosen, Sybille Dihanich, Marc PM Soutar, Helene Plun-Favreau, Rina Bandopadhyay, John Hardy, Sharon A Tooze, Mark R Cookson, Patrick A Lewis
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.
AnimalsAstrocytesAutophagyAutophagy-Related Protein-1 HomologBeclin-1Cell LineCells, CulturedHumansLeucine-Rich Repeat Serine-Threonine Protein Kinase-2MiceMicrotubule-Associated ProteinsMutationParkinson DiseaseProtein Kinase InhibitorsTOR Serine-Threonine KinasesTooze FC0011870601 Biochemistry and Cell Biology0299 Other Physical Sciences