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PLoS One. 2016 Sep 15;11(9):e0163029. doi: 10.1371/journal.pone.0163029. eCollection 2016.

Interplay between Leucine-Rich Repeat Kinase 2 (LRRK2) and p62/SQSTM-1 in Selective Autophagy.

Author information

1
Department of Biomedical Laboratory Science, College of Health, Kyungwoon University, Gumi, 39160, South Korea.
2
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.
3
Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea.
4
Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, 16499, South Korea.

Abstract

The deposit of polyubiquitinated aggregates has been implicated in the pathophysiology of Parkinson's disease (PD), and growing evidence indicates that selective autophagy plays a critical role in the clearance of ubiquitin-positive protein aggregates by autophagosomes. The selective autophagic receptor p62/SQSTM-1, which associates directly with both ubiquitin and LC3, transports ubiquitin conjugates to autophagosomes for degradation. Leucine-rich repeat kinase 2 (LRRK2), a PD-associated protein kinase, is tightly controlled by autophagy-lysosome degradation as well as by the ubiquitin-proteasome pathway. However, little is known about the degradation of ubiquitinated LRRK2 via selective autophagy. In the present study, we found that p62/SQSTM-1 physically interacts with LRRK2 as a selective autophagic receptor. The overexpression of p62 leads to the robust degradation of LRRK2 through the autophagy-lysosome pathway. In addition, LRRK2 indirectly regulates Ser351 and Ser403 phosphorylation of p62. Of particular interest, the interaction between phosphorylated p62 and Keap1 is reduced by LRRK2 overexpression. Therefore, we propose that the interplay between LRRK2 and p62 may contribute to the pathophysiological function and homeostasis of LRRK2 protein.

PMID:
27631370
PMCID:
PMC5025236
DOI:
10.1371/journal.pone.0163029
[Indexed for MEDLINE]
Free PMC Article

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