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Cell Rep. 2017 Nov 21;21(8):2171-2182. doi: 10.1016/j.celrep.2017.10.068.

S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson's Disease Models.

Author information

1
Departments of Molecular Medicine and Neuroscience and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USA; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
2
Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USA; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
3
Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
4
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
5
Departments of Molecular Medicine and Neuroscience and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
6
Departments of Molecular Medicine and Neuroscience and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USA; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: tnakamura@scripps.edu.
7
Departments of Molecular Medicine and Neuroscience and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USA; Neuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA. Electronic address: slipton@scripps.edu.

Abstract

Mutations in PARK6 (PINK1) and PARK2 (Parkin) are linked to rare familial cases of Parkinson's disease (PD). Mutations in these genes result in pathological dysregulation of mitophagy, contributing to neurodegeneration. Here, we report that environmental factors causing a specific posttranslational modification on PINK1 can mimic these genetic mutations. We describe a molecular mechanism for impairment of mitophagy via formation of S-nitrosylated PINK1 (SNO-PINK1). Mitochondrial insults simulating age- or environmental-related stress lead to increased SNO-PINK1, inhibiting its kinase activity. SNO-PINK1 decreases Parkin translocation to mitochondrial membranes, disrupting mitophagy in cell lines and human-iPSC-derived neurons. We find levels of SNO-PINK1 in brains of α-synuclein transgenic PD mice similar to those in cell-based models, indicating the pathophysiological relevance of our findings. Importantly, SNO-PINK1-mediated deficits in mitophagy contribute to neuronal cell death. These results reveal a direct molecular link between nitrosative stress, SNO-PINK1 formation, and mitophagic dysfunction that contributes to the pathogenesis of PD.

KEYWORDS:

PARK2; PARK6; PINK1; Parkin; Parkinson’s disease; S-nitrosylation; mitophagy

PMID:
29166608
PMCID:
PMC5705204
DOI:
10.1016/j.celrep.2017.10.068
[Indexed for MEDLINE]
Free PMC Article

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