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Cu, Zn-superoxide dismutase 1 (SOD1) is a novel target of Puromycin-sensitive aminopeptidase (PSA/NPEPPS): PSA/NPEPPS is a possible modifier of amyotrophic lateral sclerosis

Guijie Ren12, Zhongcai Ma1, Maria Hui3, Lili C Kudo4, Koon-Sea Hui3 and Stanislav L Karsten145*

Author Affiliations

1 Division of Neuroscience, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA

2 Department of Biochemistry and Molecular Biology, Medical College, Shandong University, Jinan, Shandong, 250012, China

3 Nathan S. Kline Institute for Psychiatric Research, New York University School of Medicine, Orangeburg, NY 10962, USA

4 NeuroInDx Inc., 1655 East 28th Street, Signal Hill, CA 90755, USA

5 Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA

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Molecular Neurodegeneration 2011, 6:29  doi:10.1186/1750-1326-6-29

Published: 7 May 2011


Accumulation of misfolded neurotoxic Cu, Zn-superoxide dismutase-1 (SOD1) protein found in both familial and sporadic amyotrophic lateral sclerosis (ALS) is recognized as an important contributing factor of neuronal cell death. However, little is known about the mechanisms controlling the accumulation and turnover of SOD1 protein. Puromycin-sensitive aminopeptidase (PSA/NPEPPS) was recently identified as a major peptidase acting on neurotoxic TAU protein and protecting against TAU-induced neurodegeneration. In addition, recent report implicated PSA/NPEPPS in the direct removal of neurotoxic polyglutamine repeats. These combined data suggest that PSA/NPEPPS might represent a novel degradation pathway targeting pathologically aggregating neurotoxic protein substrates including SOD1. Here, we report that PSA/NPEPPS directly regulates SOD1 protein abundance and clearance via proteolysis. In addition, PSA/NPEPPS expression is significantly decreased in motor neurons of both SODG93A transgenic mice and sporadic ALS patients, suggesting its possible contribution to the disease pathogenesis. These results implicate SOD1 as a new target protein of PSA/NPEPPS and point to the possible neuroprotective role of PSA/NPEPPS in ALS.