Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons.

Pardo, Carlos A.; Xu, Zuoshang; Borchelt, David R.; Price, Donald L.; Sisodia, Sangram S.; Cleveland, Don W.

doi:10.1073/pnas.92.4.954

Cited by 286 publications

(171 citation statements)

References 32 publications

Supporting

Mentioning

149

Contrasting

Unclassified

Order By: Relevance

“…Mutations in any protein that is abundant in these neurons have the probability of imposing binding of Hsps and formation of protein aggregates and depletion of free Hsps, which will ultimately tip the balance in favor of apoptosis. In addition to the reasons already discussed, motor neurons may be selectively at risk because of their high level of expression of SOD1 (27).…”

Section: Discussionmentioning

confidence: 99%

Amyotrophic lateral sclerosis: A proposed mechanism

Okado-Matsumoto

Fridovich

2002

Proc. Natl. Acad. Sci. U.S.A.

232

155

View full text Add to dashboard Cite

Missense mutations in Cu,Zn-superoxide dismutase (SOD1) account for Ϸ20% of familial amyotrophic lateral sclerosis (FALS) through some, as yet undefined, toxic gain of function that leads to gradual death of motor neurons. Mitochondrial swelling and vacuolization are early signs of incipient motor neuron death in FALS. We previously reported that SOD1 exists in the intermembrane space of mitochondria. Herein, we demonstrate that the entry of SOD1 into mitochondria depends on demetallation and that heat shock proteins (Hsp70, Hsp27, or Hsp25) block the uptake of the FALS-associated mutant SOD1 (G37R, G41D, or G93A), while having no effect on wild-type SOD1. A myotrophic lateral sclerosis (ALS) occurs in familial (FALS) and sporadic (SALS) forms and is caused by a late-onset, progressive loss of motor neurons, leading to paralysis and death. FALS and SALS are distinguishable genetically, but not clinically. Approximately 20% of cases of FALS have been associated with more than 90 different mutations in the Cu,Znsuperoxide dismutase (SOD1). These mutations are predominantly single amino acid replacements seemingly randomly scattered throughout the structure of this homodimeric 32,000-Da metalloprotein. Most of these mutant SODs retain essentially full activity, as measured in vitro, and there is overwhelming evidence for a toxic gain of function as the cause of the disease (1, 2).What common gain of function could possibly be caused by many different point mutations in SOD1 and how can the similarities in FALS and SALS be explained? In what follows we build on reports to the effect that: FALS may be caused by protein binding to mutant forms of SOD1 (3); mutant SOD1 is proapoptotic in a neuroblastoma cell line (4); the proapoptotic effect of mutant SOD1 in cultured fibroblasts was opposed by heat shock protein (Hsp) 70 (5); and mutant SOD1 binds Hsp70, Hsp40, and ␣B-crystalline (6).Because mitochondrial swelling and vacuolization are early signs of incipient motor neuron death (1, 2) and because SOD1 is found in the intermembrane space of rat (7) and yeast (8), mitochondria and SOD1 accumulate in neuronal mitochondria of transgenic mice expressing either wild type (WT) or mutant SOD1 (9); we began by examining the uptake of SOD1 into these organelles. We now demonstrate that whereas partially or wholly demetallated SOD1 is taken into mitochondria, the holo enzyme is not. This was true of both the WT and FALS-associated mutant SODs. Strikingly, a cytosolic fraction from heat-shocked mouse neuroblastoma N2A cells inhibited this uptake, whereas cytosol from N2A cells, not so treated, did not. Furthermore, whereas the uptake of mutant SOD1s was blocked by the cytosol from heat-shocked cells, the uptake of WT SOD1 was much less affected. This finding indicated that some heat shock-inducible proteins preferentially bind to mutant SOD1s and thus prevent mitochondrial uptake of the mutant SOD1s. Materials and MethodsMitochondrial Uptake of SOD1. WT and G93A SOD1s were prepared (10) and then demetallated as described (11,12)...

show abstract

Section: Discussionmentioning

confidence: 99%

Amyotrophic lateral sclerosis: A proposed mechanism

Okado-Matsumoto

Fridovich

2002

Proc. Natl. Acad. Sci. U.S.A.

232

155

View full text Add to dashboard Cite

show abstract

“…Mammalian Cu/Zn-SOD is highly expressed in the liver, kidney, and motor neurons (2,32). Knockout studies indicate that elimination of the Cu/Zn-SOD gene in rodents is associated with a variety of pathological conditions, including a decrease in life span (10) and vulnerability to motor neuron loss after axonal injury (33).…”

Section: Discussionmentioning

confidence: 99%

Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD: a proteomic analysis

Son¹,

Kojima²,

Inagi³

et al. 2008

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Son D, Kojima I, Inagi R, Matsumoto M, Fujita T, Nangaku M. Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD: a proteomic analysis. Am J Physiol Renal Physiol 294: F62-F72, 2008. First published October 24, 2007 doi:10.1152/ajprenal.00113.2007.-Accumulating evidence suggests a pathogenic role of chronic hypoxia in various kidney diseases. Chronic hypoxia in the kidney was induced by unilateral renal artery stenosis, followed 7 days later by observation of tubulointerstitial injury. Proteomic analysis of the hypoxic kidney found various altered proteins. Increased proteins included lipocortin-5, calgizzarin, ezrin, and transferrin, whereas the decreased proteins were ␣ 2u-globulin PGCL1, eukaryotic translation elongation factor 1␣ 2, and Cu/Zn superoxide dismutase (SOD1). Among these proteins, we focused on Cu/Zn-SOD, a crucial antioxidant. Western blot analysis and real-time quantitative PCR analysis confirmed the downregulation of Cu/Zn-SOD in the chronic hypoxic kidney. Furthermore, our laser capture microdissection system showed that the expression of Cu/Zn-SOD was predominant in the tubulointerstitium and was decreased by chronic hypoxia. The tubulointerstitial injury estimated by histology and immunohistochemical markers was ameliorated by tempol, a SOD mimetic. This amelioration was associated with a decrease in levels of the oxidative stress markers 4-hydroxyl-2-nonenal and nitrotyrosine. Our in vitro studies utilizing cultured tubular cells revealed a role of TNF-␣ in downregulation of Cu/Zn-SOD. Since the administration of anti-TNF-␣ antibody ameliorated Cu/Zn-SOD suppression, TNF-␣ seems to be one of the suppressants of Cu/Zn-SOD. In conclusion, our proteomic analysis revealed a decrease in Cu/Zn-SOD, at least partly by TNF-␣, in the chronic hypoxic kidney. This study, for the first time, uncovered maladaptive suppression of Cu/Zn-SOD as a mediator of a vicious cycle of oxidative stress and subsequent renal injury induced by chronic hypoxia. chronic kidney failure; oxidative stress ONCE RENAL DAMAGE REACHES a certain threshold, the progression of renal disease is consistent, irreversible and largely independent of the initial insult. The final common pathway in this process has been closely studied. The chronic hypoxia hypothesis, proposed by Fine et al. (11), emphasizes chronic ischemic damage in the tubulointerstitium as a final common pathway in end-stage kidney injury. Since its introduction, this fascinating hypothesis has been intensively investigated by many investigators (9,20,24). Despite intensive efforts to elucidate the pathomechanisms of chronic hypoxia on kidney damage, however, their complexity has hampered investigations and details remain scarce. Among others, mechanisms proposed to date include transdifferentiation (22), cell death (40 -42), production of extracellular matrix (26,27), and so on.Advances in proteomics technology offer promise to substantially improve our understanding and treatment of the molecular basis of disease. In particular, deciphering the a...

show abstract

“…Proteins were separated on 12% SDS/PAGE gels and transferred onto PVDF membranes. Membranes were incubated with a rabbit polyclonal anti-SOD1 antiserum (34) followed by an HRP-conjugated anti-rabbit IgG secondary antibody before visualization with ECL plus solution (GE Biosciences, Little Chalfont, U.K.). Protein signals were quantified on Typhoon 9410, using Image Quant program (GE Biosciences).…”

Section: Methodsmentioning

confidence: 99%