TY - JOUR
T1 - Advanced glycation endproduct-modified superoxide dismutase-1 (SOD1)-positive inclusions are common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutations and transgenic mice expressing human SOD1 with a G85R mutation
AU - Kato, S.
AU - Horiuchi, Seiko
AU - Liu, Jian
AU - Cleveland, Don W.
AU - Shibata, Noriyuki
AU - Nakashima, Kenji
AU - Nagai, Ryoji
AU - Hirano, Asao
AU - Takikawa, Miki
AU - Kato, Masako
AU - Nakano, Imaharu
AU - Ohama, Eisaku
N1 - Funding Information:
Acknowledgements The authors express their appreciation to Dr. Kohtaro Asayama for kindly providing antibodies against SOD1 and SOD2; Dr. Hiroyasu Esumi, for the antibodies to nNOS and iNOS; Dr. James E. Goldman, for the antibody to αB-crystallin; Dr. Shu-Hui Yen, for the antibodies against ubiquitin and PHF (Ab39); Dr Masaya Oda, for the antibody to GS; Dr. Takeshi Iwatsubo, for the antibody against α-synuclein, and Dr. Tadashi Kurihara, for the antibody to CNP. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.
PY - 2000
Y1 - 2000
N2 - To clarify the biological significance of the neuronal Lewy body-like hyaline inclusions and astrocytic hyaline inclusions characteristically found in patients with familial amyotrophic lateral sclerosis with superoxide dismutase-1 (SOD1) gene mutations and in transgenic mice expressing human SOD1 with G85R mutation, the detailed protein composition in both types of inclusions was immunohistochemically analyzed using 45 different antibodies. Both types of inclusions had very strong immunoreactivity for SOD1. The SOD1-positive inclusions in both cell types were also immunoreactive for the insoluble advanced glycation endproducts (AGEs) such as N(ε)-(carboxymethyl)lysine (CML), pyrraline and pentosidine: both inclusions in both conditions were ultrastructurally composed of the granule-coated fibrils that had immunoreactivities to CML and pyrraline. Both types of inclusions were negative for stress-response proteins (SRPs), 4-hydroxy-2-nonenal (HNE), acrolein, nitric oxide synthases (NOSs) and nitrotyrosine as representative markers of oxidative stress. The neurons and astrocytes of the normal individuals and non-transgenic mice showed no significant immunoreactivity for SOD1, AGEs, SRPs, HNE, acrolein, NOSs or nitrotyrosine. Our results suggest that a portion of the SOD1 composing both type of inclusions, probably toxic mutant SOD1, is modified by the AGEs, and that the formation of the AGE-modified SOD1 is one of the mechanisms responsible for the aggregation involving no significant oxidative mechanisms.
AB - To clarify the biological significance of the neuronal Lewy body-like hyaline inclusions and astrocytic hyaline inclusions characteristically found in patients with familial amyotrophic lateral sclerosis with superoxide dismutase-1 (SOD1) gene mutations and in transgenic mice expressing human SOD1 with G85R mutation, the detailed protein composition in both types of inclusions was immunohistochemically analyzed using 45 different antibodies. Both types of inclusions had very strong immunoreactivity for SOD1. The SOD1-positive inclusions in both cell types were also immunoreactive for the insoluble advanced glycation endproducts (AGEs) such as N(ε)-(carboxymethyl)lysine (CML), pyrraline and pentosidine: both inclusions in both conditions were ultrastructurally composed of the granule-coated fibrils that had immunoreactivities to CML and pyrraline. Both types of inclusions were negative for stress-response proteins (SRPs), 4-hydroxy-2-nonenal (HNE), acrolein, nitric oxide synthases (NOSs) and nitrotyrosine as representative markers of oxidative stress. The neurons and astrocytes of the normal individuals and non-transgenic mice showed no significant immunoreactivity for SOD1, AGEs, SRPs, HNE, acrolein, NOSs or nitrotyrosine. Our results suggest that a portion of the SOD1 composing both type of inclusions, probably toxic mutant SOD1, is modified by the AGEs, and that the formation of the AGE-modified SOD1 is one of the mechanisms responsible for the aggregation involving no significant oxidative mechanisms.
KW - Advanced glycation endproducts
KW - Familial amyotrophic lateral sclerosis
KW - G85R transgenic mice
KW - Granule-coated fibrils
KW - Superoxide dismutase-1
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U2 - 10.1007/s004010000226
DO - 10.1007/s004010000226
M3 - Article
C2 - 11045671
AN - SCOPUS:0033823740
SN - 0001-6322
VL - 100
SP - 490
EP - 505
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 5
ER -