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

Manzoni, C., Mamais, A., Roosen, D. A., Dihanich, S., Soutar, M. P. M., Plun-Favreau, H., Bandopadhyay, R., Hardy, J., Tooze, S. A., Cookson, M. R. and Lewis, P. A. (2016) mTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1. Scientific Reports, 6. 35106. ISSN 2045-2322 doi: 10.1038/srep35106

Abstract/Summary

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 identi ed. To investigate the signalling events through which LRRK2 acts to in uence 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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/67483
Identification Number/DOI	10.1038/srep35106
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Publisher	Nature Publishing Group
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