4.8 Article

Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes

期刊

CURRENT BIOLOGY
卷 31, 期 10, 页码 2140-+

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CELL PRESS
DOI: 10.1016/j.cub.2021.02.061

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资金

  1. German Research Foundation (DFG) [BO 5434/1-1]
  2. National Institutes of Health [R37 NS060698]
  3. Michael J. Fox Foundation [15100]

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Mutations in the LRRK2 gene associated with Parkinson's disease lead to defects in autophagosome transport, impairing effective degradation of autophagosomal cargo in neurons.
Parkinson's disease-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. 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, and the effect was reversed by genetic or pharmacological inhibition of LRRK2. 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 the motor adaptor JNKinteracting protein 4 (JIP4) to the autophagosomal membrane, inducing abnormal activation of kinesin that we propose leads to an unproductive tug of war between anterograde and retrograde motors. Disruption of autophagosome transport correlated with a significant defect in autophagosome acidification, suggesting that the observed transport deficit impairs effective degradation of autophagosomal cargo in neurons. Our results robustly link increased LRRK2 kinase activity to defects in autophagosome transport and maturation, further implicating defective autophagy in the pathogenesis of Parkinson's disease.

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