The pathogenic effect of LRRK2-G2019S mutation: Impairment of neuronal autophagy in Parkinson’s Disease
Final Report Abstract
Parkinson’s disease (PD)-causing mutations in the leucine-rich repeat kinase 2 (LRRK2) gene hyperactivate LRRK2 kinase activity and cause increased phosphorylation of Rab GTPases, important regulators of intracellular trafficking. This project aimed at investigating the effect of LRRK2 hyperactivation on neuronal autophagy, a process that is highly dependent on efficient axonal transport. We found that the most common LRRK2 mutation, LRRK2-G2019S, dramatically reduces the processivity of autophagosome transport in neurons in a kinase-dependent manner. This effect was consistent across an overexpression model, neurons from a G2019S knockin mouse, and human induced pluripotent stem cell (iPSC)-derived neurons gene edited to express the G2019S mutation. Furthermore, LRRK2 hyperactivation induced by overexpression of Rab29, a known activator of LRRK2 kinase, disrupted autophagosome transport to a similar extent. Mechanistically, we found that hyperactive LRRK2 recruits JIP4, a motor adaptor known to bind to LRRK2-phosphorylated Rab proteins, to the autophagosomal membrane. Increased JIP4 levels induced abnormal recruitment and activation of kinesin-1, which we propose results in an unproductive tug-of-war between anterograde and retrograde motors bound to autophagosomes. Disruption of autophagosome transport correlated with defective autophagosome maturation, suggesting that hyperactive LRRK2 may impair efficient degradation of autophagosomal cargo. Our work demonstrates that LRRK2 hyperactivation is sufficient to induce defects in autophagosome transport and maturation, further establishing a role of defective autophagy in the pathogenesis of PD.
Publications
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(2019). Vesicular degradation pathways in neurons: at the crossroads of autophagy and endo-lysosomal degradation. Current Opinion in Neurobiology
Boecker, C.A., and Holzbaur, E.L.F.
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(2020). ToolBox: Live Imaging of intracellular organelle transport in iPSC-derived neurons. Traffic
Boecker, C.A., Olenick, M.A., Gallagher, E.R., Ward, M.E., and Holzbaur, E.L.F.
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(2020). TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model. eLife
Sase, S., Almad, A.A., Boecker, C.A., Guedes-Dias, P., Li, J.J., Takanohashi, A., Patel, A., McCaffrey, T., Patel, H., Sirdeshpande, D., Curiel J., Liu J.S., Padiath, Q., Holzbaur E.L.F., Scherer S., Vanderver, A.
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(2021). Actin cables and comet tails organize mitochondrial networks in mitosis. Nature
Moore, A.S., Coscia, S.M., Simpson, C.L., Ortega, F.E., Wait, E.C., Heddleston, J.M., Nirschl, J.J., Obara, C.J., Guedes-Dias, P., Boecker, C.A., Chew, T.-L., Theriot, J.A., Lippincott-Schwartz, J., and Holzbaur, E.L.F.
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(2021). Hyperactive LRRK2 kinase impairs the trafficking of axonal autophagosomes. Autophagy
Boecker, C.A., and E.L.F. Holzbaur
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(2021). Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes. Current Biology
Boecker, C.A., Goldsmith, J., Dou, D., Cajka, G.G., Holzbaur, E.L.F.
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(2021). Structural Basis for Membrane Recruitment of ATG16L1 by WIPI2 in Autophagy. eLife
Strong, L.M., Chang, C., J.F. Riley, Boecker, C.A., Flower, T.G., C.Z. Buffalo, X. Ren, A.K.H. Stavoe, E.L.F. Holzbaur, and J.H. Hurley
