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Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation.
Hum Mol Genet 2013; 22(22):4545-61HM

Abstract

LRRK2 G2019S mutation is the most common genetic cause of Parkinson's disease (PD). Cellular pathology caused by this mutant is associated with mitochondrial dysfunction and augmented autophagy. However, the underlying mechanism is not known. In this study, we determined whether blocking excessive mitochondrial fission could reduce cellular damage and neurodegeneration induced by the G2019S mutation. In both LRRK2 G2019S-expressing cells and PD patient fibroblasts carrying this specific mutant, treatment with P110, a selective peptide inhibitor of fission dynamin-related protein 1 (Drp1) recently developed in our lab, reduced mitochondrial fragmentation and damage, and corrected excessive autophagy. LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation. A site-directed mutant, Drp1(T595A), corrected mitochondrial fragmentation, improved mitochondrial mass and suppressed excessive autophagy in both cells expressing LRRK2 G2019S and PD patient fibroblasts carrying the mutant. Further, in dopaminergic neurons derived from LRRK2 G2019S PD patient-induced pluripotent stem cells, we demonstrated that either P110 treatment or expression of Drp1(T595A) reduced mitochondrial impairment, lysosomal hyperactivity and neurite shortening. Together, we propose that inhibition of Drp1-mediated excessive mitochondrial fission might be a strategy for treatment of PD relevant to LRRK2 G2019S mutation.

Authors+Show Affiliations

Department of Physiology and Biophysics and.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23813973

Citation

Su, Yu-Chin, and Xin Qi. "Inhibition of Excessive Mitochondrial Fission Reduced Aberrant Autophagy and Neuronal Damage Caused By LRRK2 G2019S Mutation." Human Molecular Genetics, vol. 22, no. 22, 2013, pp. 4545-61.
Su YC, Qi X. Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet. 2013;22(22):4545-61.
Su, Y. C., & Qi, X. (2013). Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Human Molecular Genetics, 22(22), pp. 4545-61. doi:10.1093/hmg/ddt301.
Su YC, Qi X. Inhibition of Excessive Mitochondrial Fission Reduced Aberrant Autophagy and Neuronal Damage Caused By LRRK2 G2019S Mutation. Hum Mol Genet. 2013 Nov 15;22(22):4545-61. PubMed PMID: 23813973.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. AU - Su,Yu-Chin, AU - Qi,Xin, Y1 - 2013/06/27/ PY - 2013/7/2/entrez PY - 2013/7/3/pubmed PY - 2014/6/4/medline SP - 4545 EP - 61 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 22 IS - 22 N2 - LRRK2 G2019S mutation is the most common genetic cause of Parkinson's disease (PD). Cellular pathology caused by this mutant is associated with mitochondrial dysfunction and augmented autophagy. However, the underlying mechanism is not known. In this study, we determined whether blocking excessive mitochondrial fission could reduce cellular damage and neurodegeneration induced by the G2019S mutation. In both LRRK2 G2019S-expressing cells and PD patient fibroblasts carrying this specific mutant, treatment with P110, a selective peptide inhibitor of fission dynamin-related protein 1 (Drp1) recently developed in our lab, reduced mitochondrial fragmentation and damage, and corrected excessive autophagy. LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation. A site-directed mutant, Drp1(T595A), corrected mitochondrial fragmentation, improved mitochondrial mass and suppressed excessive autophagy in both cells expressing LRRK2 G2019S and PD patient fibroblasts carrying the mutant. Further, in dopaminergic neurons derived from LRRK2 G2019S PD patient-induced pluripotent stem cells, we demonstrated that either P110 treatment or expression of Drp1(T595A) reduced mitochondrial impairment, lysosomal hyperactivity and neurite shortening. Together, we propose that inhibition of Drp1-mediated excessive mitochondrial fission might be a strategy for treatment of PD relevant to LRRK2 G2019S mutation. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/23813973/Inhibition_of_excessive_mitochondrial_fission_reduced_aberrant_autophagy_and_neuronal_damage_caused_by_LRRK2_G2019S_mutation_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddt301 DB - PRIME DP - Unbound Medicine ER -