Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2011

Open Access 01-12-2011 | Short report

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

Authors: Guijie Ren, Zhongcai Ma, Maria Hui, Lili C Kudo, Koon-Sea Hui, Stanislav L Karsten

Published in: Molecular Neurodegeneration | Issue 1/2011

Login to get access

Abstract

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 SOD G93A 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.
Appendix
Available only for authorised users
Literature
1.
Bruijn LI, Miller TM, Cleveland DW: Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci. 2004, 27: 723-749. 10.1146/annurev.neuro.27.070203.144244.PubMedCrossRef
2.
Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX, et al: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993, 362: 59-62. 10.1038/362059a0.PubMedCrossRef
3.
Rothstein JD: Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 2009, 65 (Suppl 1): S3-S9.PubMedCrossRef
4.
Beleza-Meireles A, Al-Chalabi A: Genetic studies of amyotrophic lateral sclerosis: controversies and perspectives. Amyotroph Lateral Scler. 2009, 10: 1-14. 10.1080/17482960802585469.PubMedCrossRef
5.
Valdmanis PN, Daoud H, Dion PA, Rouleau GA: Recent advances in the genetics of amyotrophic lateral sclerosis. Curr Neurol Neurosci Rep. 2009, 9: 198-205. 10.1007/s11910-009-0030-9.PubMedCrossRef
6.
Chattopadhyay M, Valentine JS: Aggregation of copper-zinc superoxide dismutase in familial and sporadic ALS. Antioxid Redox Signal. 2009, 11: 1603-1614. 10.1089/ars.2009.2536.PubMedPubMedCentralCrossRef
7.
Shaw BF, Valentine JS: How do ALS-associated mutations in superoxide dismutase 1 promote aggregation of the protein?. Trends Biochem Sci. 2007, 32: 78-85. 10.1016/j.tibs.2006.12.005.PubMedCrossRef
8.
Shibata N, Hirano A, Kobayashi M, Siddique T, Deng HX, Hung WY, Kato T, Asayama K: Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement. J Neuropathol Exp Neurol. 1996, 55: 481-490. 10.1097/00005072-199604000-00011.PubMedCrossRef
9.
Wang J, Xu G, Borchelt DR: High molecular weight complexes of mutant superoxide dismutase 1: age-dependent and tissue-specific accumulation. Neurobiol Dis. 2002, 9: 139-148. 10.1006/nbdi.2001.0471.PubMedCrossRef
10.
Kato S, Takikawa M, Nakashima K, Hirano A, Cleveland DW, Kusaka H, Shibata N, Kato M, Nakano I, Ohama E: New consensus research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 (SOD1) gene mutations: inclusions containing SOD1 in neurons and astrocytes. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000, 1: 163-184. 10.1080/14660820050515160.PubMedCrossRef
11.
Bosco DA, Morfini G, Karabacak NM, Song Y, Gros-Louis F, Pasinelli P, Goolsby H, Fontaine BA, Lemay N, McKenna-Yasek D, et al: Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci. 2010, 13: 1396-1403. 10.1038/nn.2660.PubMedPubMedCentralCrossRef
12.
Forsberg K, Jonsson PA, Andersen PM, Bergemalm D, Graffmo KS, Hultdin M, Jacobsson J, Rosquist R, Marklund SL, Brannstrom T: Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients. PLoS One. 2010, 5: e11552-10.1371/journal.pone.0011552.PubMedPubMedCentralCrossRef
13.
Aguzzi A, O'Connor T: Protein aggregation diseases: pathogenicity and therapeutic perspectives. Nat Rev Drug Discov. 2010, 9: 237-248. 10.1038/nrd3050.PubMedCrossRef
14.
Ballatore C, Lee VM, Trojanowski JQ: Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci. 2007, 8: 663-672.PubMedCrossRef
15.
Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke-Iqbal I: Mechanisms of tau-induced neurodegeneration. Acta Neuropathol. 2009, 118: 53-69. 10.1007/s00401-009-0486-3.PubMedPubMedCentralCrossRef
16.
Spires-Jones TL, Stoothoff WH, de Calignon A, Jones PB, Hyman BT: Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci. 2009, 32: 150-159. 10.1016/j.tins.2008.11.007.PubMedCrossRef
17.
Gruzman A, Wood WL, Alpert E, Prasad MD, Miller RG, Rothstein JD, Bowser R, Hamilton R, Wood TD, Cleveland DW, et al: Common molecular signature in SOD1 for both sporadic and familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 2007, 104: 12524-12529. 10.1073/pnas.0705044104.PubMedPubMedCentralCrossRef
18.
Matsumoto S, Kusaka H, Ito H, Shibata N, Asayama T, Imai T: Sporadic amyotrophic lateral sclerosis with dementia and Cu/Zn superoxide dismutase-positive Lewy body-like inclusions. Clin Neuropathol. 1996, 15: 41-46.PubMed
19.
Shibata N, Hirano A, Kobayashi M, Sasaki S, Kato T, Matsumoto S, Shiozawa Z, Komori T, Ikemoto A, Umahara T, et al: Cu/Zn superoxide dismutase-like immunoreactivity in Lewy body-like inclusions of sporadic amyotrophic lateral sclerosis. Neurosci Lett. 1994, 179: 149-152. 10.1016/0304-3940(94)90956-3.PubMedCrossRef
20.
Kabashi E, Valdmanis PN, Dion P, Rouleau GA: Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis?. Ann Neurol. 2007, 62: 553-559. 10.1002/ana.21319.PubMedCrossRef
21.
Xia X, Zhou H, Huang Y, Xu Z: Allele-specific RNAi selectively silences mutant SOD1 and achieves significant therapeutic benefit in vivo. Neurobiol Dis. 2006, 23: 578-586. 10.1016/j.nbd.2006.04.019.PubMedCrossRef
22.
Karsten SL, Sang TK, Gehman LT, Chatterjee S, Liu J, Lawless GM, Sengupta S, Berry RW, Pomakian J, Oh HS, et al: A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration. Neuron. 2006, 51: 549-560. 10.1016/j.neuron.2006.07.019.PubMedCrossRef
23.
Sengupta S, Horowitz PM, Karsten SL, Jackson GR, Geschwind DH, Fu Y, Berry RW, Binder LI: Degradation of tau protein by puromycin-sensitive aminopeptidase in vitro. Biochemistry. 2006, 45: 15111-15119. 10.1021/bi061830d.PubMedCrossRef
24.
Yanagi K, Tanaka T, Kato K, Sadik G, Morihara T, Kudo T, Takeda M: Involvement of puromycin-sensitive aminopeptidase in proteolysis of tau protein in cultured cells, and attenuated proteolysis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) mutant tau. Psychogeriatrics. 2009, 9: 157-166. 10.1111/j.1479-8301.2010.00307.x.PubMedCrossRef
25.
Bhutani N, Venkatraman P, Goldberg AL: Puromycin-sensitive aminopeptidase is the major peptidase responsible for digesting polyglutamine sequences released by proteasomes during protein degradation. EMBO J. 2007, 6: 1385-1396.CrossRef
26.
Menzies FM, Hourez R, Imarisio S, Raspe M, Sadiq O, Chandraratna D, O'Kane C, Rock KL, Reits E, Goldberg AL, et al: Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy. Hum Mol Genet. 2010, 19: 4573-4586. 10.1093/hmg/ddq385.PubMedPubMedCentralCrossRef
27.
Glynn MW, McAllister AK: Immunocytochemistry and quantification of protein colocalization in cultured neurons. Nat Protoc. 2006, 1: 1287-1296. 10.1038/nprot.2006.220.PubMedCrossRef
28.
Kita H, Carmichael J, Swartz J, Muro S, Wyttenbach A, Matsubara K, Rubinsztein DC, Kato K: Modulation of polyglutamine-induced cell death by genes identified by expression profiling. Hum Mol Genet. 2002, 11: 2279-2287. 10.1093/hmg/11.19.2279.PubMedCrossRef
29.
Kudo LC, Parfenova L, Ren G, Vi N, Hui M, Ma Z, Lau K, Gray M, Bardag-Gorce F, Wiedau-Pazos M, et al: Puromycin-sensitive aminopeptidase (PSA/NPEPPS) impedes development of neuropathology in hPSA/TAUP301L double-transgenic mice. Hum Mol Genet. 2011, 20: 1820-33. 10.1093/hmg/ddr065.PubMedCrossRef
30.
Hui KS, Hui M: An automatic continuous-flow aminopeptidase detector and its applications. Anal Biochem. 1996, 242: 271-273. 10.1006/abio.1996.0464.PubMedCrossRef
31.
Hui KS, Lajtha A: Proteinases and peptidases. Neuromethods. Edited by: Boulton AA, Baker GB, Yu PH. 1986, New Jersey: Humana Press, V: 421-450. 1
32.
Hui KS, Saito M, Hui M: A novel neuron-specific aminopeptidase in rat brain synaptosomes. Its identification, purification, and characterization. J Biol Chem. 1998, 273: 31053-31060. 10.1074/jbc.273.47.31053.PubMedCrossRef
33.
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al: Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994, 264: 1772-1775. 10.1126/science.8209258.PubMedCrossRef
34.
Epstein CJ, Avraham KB, Lovett M, Smith S, Elroy-Stein O, Rotman G, Bry C, Groner Y: Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. Proc Natl Acad Sci USA. 1987, 84: 8044-8048. 10.1073/pnas.84.22.8044.PubMedPubMedCentralCrossRef
35.
Liu HN, Sanelli T, Horne P, Pioro EP, Strong MJ, Rogaeva E, Bilbao J, Zinman L, Robertson J: Lack of evidence of monomer/misfolded superoxide dismutase-1 in sporadic amyotrophic lateral sclerosis. Ann Neurol. 2009, 66: 75-80. 10.1002/ana.21704.PubMedCrossRef
36.
Kerman A, Liu HN, Croul S, Bilbao J, Rogaeva E, Zinman L, Robertson J, Chakrabartty A: Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form. Acta Neuropathol. 2010, 119: 335-344. 10.1007/s00401-010-0646-5.PubMedCrossRef
37.
Barmada S, Finkbeiner S: Bringing SOD1 into the fold. Nat Neurosci. 2010, 13: 1303-1304. 10.1038/nn1110-1303.PubMedCrossRef
38.
Kudo LC, Parfenova L, Vi N, Lau K, Pomakian J, Valdmanis P, Rouleau GA, Vinters HV, Wiedau-Pazos M, Karsten SL: Integrative gene-tissue microarray-based approach for identification of human disease biomarkers: application to amyotrophic lateral sclerosis. Hum Mol Genet. 2010, 19: 3233-3253. 10.1093/hmg/ddq232.PubMedCrossRef
Metadata
Title
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
Authors
Guijie Ren
Zhongcai Ma
Maria Hui
Lili C Kudo
Koon-Sea Hui
Stanislav L Karsten
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2011
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/1750-1326-6-29

Other articles of this Issue 1/2011

Molecular Neurodegeneration 1/2011 Go to the issue

Research article

A new role for interferon gamma in neural stem/precursor cell dysregulation

Research article

Renin angiotensin system and gender differences in dopaminergic degeneration

Research article

T cell mediated cerebral hemorrhages and microhemorrhages during passive Aβ immunization in APPPS1 transgenic mice

Research article

Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

Research article

MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease

Research article

Dopamine and α-synuclein dysfunction in Smad3 null mice