Format

Send to

Choose Destination
EMBO Rep. 2018 Mar;19(3). pii: e44860. doi: 10.15252/embr.201744860. Epub 2018 Jan 25.

Knockdown of the mitochondria-localized protein p13 protects against experimental parkinsonism.

Author information

1
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
2
Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Osaka University, Suita, Osaka, Japan.
3
Research Fellowships for Young Scientists of the Japan Society for the Promotion of Science, Chiyoda, Tokyo, Japan.
4
Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.
5
Animal Resource Center for Infectious Diseases, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
6
Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara, Japan.
7
Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
8
Toneyama National Hospital, Toyonaka, Osaka, Japan.
9
Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University Kanazawa University Hamamatsu University School of Medicine Chiba University and University of Fukui, Suita, Osaka, Japan.
10
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan shintani@phs.osaka-u.ac.jp hasimoto@phs.osaka-u.ac.jp.
11
iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
12
Division of Bioscience, Institute for Datability Science, Osaka University, Suita, Osaka, Japan.

Abstract

Mitochondrial dysfunction in the nigrostriatal dopaminergic system is a critical hallmark of Parkinson's disease (PD). Mitochondrial toxins produce cellular and behavioural dysfunctions resembling those in patients with PD Causative gene products for familial PD play important roles in mitochondrial function. Therefore, targeting proteins that regulate mitochondrial integrity could provide convincing strategies for PD therapeutics. We have recently identified a novel 13-kDa protein (p13) that may be involved in mitochondrial oxidative phosphorylation. In the current study, we examine the mitochondrial function of p13 and its involvement in PD pathogenesis using mitochondrial toxin-induced PD models. We show that p13 overexpression induces mitochondrial dysfunction and apoptosis. p13 knockdown attenuates toxin-induced mitochondrial dysfunction and apoptosis in dopaminergic SH-SY5Y cells via the regulation of complex I. Importantly, we generate p13-deficient mice using the CRISPR/Cas9 system and observe that heterozygous p13 knockout prevents toxin-induced motor deficits and the loss of dopaminergic neurons in the substantia nigra. Taken together, our results suggest that manipulating p13 expression may be a promising avenue for therapeutic intervention in PD.

KEYWORDS:

Parkinson's disease; cell death; complex I; mitochondria; p13

PMID:
29371327
PMCID:
PMC5836091
[Available on 2019-03-01]
DOI:
10.15252/embr.201744860
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center