Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by motoneuron loss. Some familial cases (fALS) are linked to mutations of superoxide dismutase type-1 (SOD1), an antioxidant enzyme whose activity is preserved in most mutant forms. Owing to the similarities in sporadic and fALS forms, mutant SOD1 animal and cellular models are a useful tool to study the disease. In transgenic mice expressing either wild-type (wt) human SOD1 or mutant G93A-SOD1, we found that wtSOD1 was present in cytoplasm and in nuclei of motoneurons, whereas mutant SOD1 was mainly cytoplasmic. Similar results were obtained in immortalized motoneurons (NSC34 cells) expressing either wtSOD1 or G93A-SOD1. Analyzing the proteasome activity, responsible for misfolded protein clearance, in the two subcellular compartments, we found proteasome impairment only in the cytoplasm. The effect of G93A-SOD1 exclusion from nuclei was then analyzed after oxidative stress. Cells expressing G93A-SOD1 showed a higher DNA damage compared with those expressing wtSOD1, possibly because of a loss of nuclear protection. The toxicity of mutant SOD1 might, therefore, arise from an initial misfolding (gain of function) reducing nuclear protection from the active enzyme (loss of function in the nuclei), a process that may be involved in ALS pathogenesis.
| Original language | English |
|---|---|
| Pages (from-to) | 1604-1618 |
| Number of pages | 15 |
| Journal | Human Molecular Genetics |
| Volume | 16 |
| Issue number | 13 |
| DOIs | |
| Publication status | Published - Jul 2007 |
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ASJC Scopus subject areas
- Genetics
Cite this
Mutation of SOD1 in ALS : A gain of a loss of function. / Sau, Daniela; De Biasi, Silvia; Vitellaro-Zuccarello, Laura; Riso, Patrizia; Guarnieri, Serena; Porrini, Marisa; Simeoni, Silvia; Crippa, Valeria; Onesto, Elisa; Palazzolo, Isabella; Rusmini, Paola; Bolzoni, Elena; Bendotti, Caterina; Poletti, Angelo.
In: Human Molecular Genetics, Vol. 16, No. 13, 07.2007, p. 1604-1618.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mutation of SOD1 in ALS
T2 - A gain of a loss of function
AU - Sau, Daniela
AU - De Biasi, Silvia
AU - Vitellaro-Zuccarello, Laura
AU - Riso, Patrizia
AU - Guarnieri, Serena
AU - Porrini, Marisa
AU - Simeoni, Silvia
AU - Crippa, Valeria
AU - Onesto, Elisa
AU - Palazzolo, Isabella
AU - Rusmini, Paola
AU - Bolzoni, Elena
AU - Bendotti, Caterina
AU - Poletti, Angelo
PY - 2007/7
Y1 - 2007/7
N2 - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by motoneuron loss. Some familial cases (fALS) are linked to mutations of superoxide dismutase type-1 (SOD1), an antioxidant enzyme whose activity is preserved in most mutant forms. Owing to the similarities in sporadic and fALS forms, mutant SOD1 animal and cellular models are a useful tool to study the disease. In transgenic mice expressing either wild-type (wt) human SOD1 or mutant G93A-SOD1, we found that wtSOD1 was present in cytoplasm and in nuclei of motoneurons, whereas mutant SOD1 was mainly cytoplasmic. Similar results were obtained in immortalized motoneurons (NSC34 cells) expressing either wtSOD1 or G93A-SOD1. Analyzing the proteasome activity, responsible for misfolded protein clearance, in the two subcellular compartments, we found proteasome impairment only in the cytoplasm. The effect of G93A-SOD1 exclusion from nuclei was then analyzed after oxidative stress. Cells expressing G93A-SOD1 showed a higher DNA damage compared with those expressing wtSOD1, possibly because of a loss of nuclear protection. The toxicity of mutant SOD1 might, therefore, arise from an initial misfolding (gain of function) reducing nuclear protection from the active enzyme (loss of function in the nuclei), a process that may be involved in ALS pathogenesis.
AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by motoneuron loss. Some familial cases (fALS) are linked to mutations of superoxide dismutase type-1 (SOD1), an antioxidant enzyme whose activity is preserved in most mutant forms. Owing to the similarities in sporadic and fALS forms, mutant SOD1 animal and cellular models are a useful tool to study the disease. In transgenic mice expressing either wild-type (wt) human SOD1 or mutant G93A-SOD1, we found that wtSOD1 was present in cytoplasm and in nuclei of motoneurons, whereas mutant SOD1 was mainly cytoplasmic. Similar results were obtained in immortalized motoneurons (NSC34 cells) expressing either wtSOD1 or G93A-SOD1. Analyzing the proteasome activity, responsible for misfolded protein clearance, in the two subcellular compartments, we found proteasome impairment only in the cytoplasm. The effect of G93A-SOD1 exclusion from nuclei was then analyzed after oxidative stress. Cells expressing G93A-SOD1 showed a higher DNA damage compared with those expressing wtSOD1, possibly because of a loss of nuclear protection. The toxicity of mutant SOD1 might, therefore, arise from an initial misfolding (gain of function) reducing nuclear protection from the active enzyme (loss of function in the nuclei), a process that may be involved in ALS pathogenesis.
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UR - http://www.scopus.com/inward/citedby.url?scp=34447329567&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddm110
DO - 10.1093/hmg/ddm110
M3 - Article
C2 - 17504823
AN - SCOPUS:34447329567
VL - 16
SP - 1604
EP - 1618
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 13
ER -