Protein-bound crotonaldehyde accumulates in the spinal cord of superoxide dismutase-1 mutation-associated familial amyotrophic lateral sclerosis and its transgenic mouse model.
Growing evidence documents oxidative stress involvement in ALS. We previously demonstrated accumulation of a protein-bound form of the highly toxic lipid peroxidation product crotonaldehyde (CRA) in the spinal cord of sporadic ALS patients. In the present study, to the determine the role for CRA in the disease processes of superoxide dismutase-1 (SOD1) mutation-associated familial ALS (FALS), we performed immunohistochemical and semi-quantitative cell count analyses of protein-bound CRA (P-CRA) in the spinal cord of SOD1-mutated FALS and its transgenic mouse model. Immunohistochemical analysis revealed increased P-CRA immunoreactivity in the spinal cord of the FALS patients and the transgenic mice compared to their respective controls. In the FALS patients, P-CRA immunoreactivity was localized in almost all of the chromatolytic motor neurons, neurofilamentous conglomerates, spheroids, cordlike swollen axons, reactive astrocytes and microglia, and the surrounding neuropil in the affected areas represented by the anterior horns. In the transgenic mice, P-CRA immunoreactivity was localized in only a few ventral horn glia in the presymptomatic stage, in almost all of the vacuolated motor neurons and cordlike swollen axons and some of the ventral horn reactive astrocytes and microglia in the onset stage, and in many of the ventral horn reactive astrocytes and microglia in the advanced stage. Cell count analysis on mouse spinal cord sections disclosed a statistically significant increase in the density of P-CRA-immunoreactive glia in the ventral horns of the young to old G93A mice compared to the age-matched control mice. The present results indicate that enhanced CRA formation occurs in motor neurons and reactive glia in the spinal cord of SOD1-mutated FALS and its transgenic mouse model as well as sporadic ALS, sug- gesting implications for CRA in the pathomechanism common to these forms of ALS.
Shibata
Noriyuki
N
Department of Pathology, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan. shibatan@research.twmu.ac.jp
Kawaguchi
Motoko
M
Uchida
Koji
K
Kakita
Akiyoshi
A
Takahashi
Hitoshi
H
Nakano
Ryoichi
R
Fujimura
Harutoshi
H
Sakoda
Saburo
S
Ihara
Yuetsu
Y
Nobukuni
Keigo
K
Takehisa
Yasushi
Y
Kuroda
Shigetoshi
S
Kokubo
Yasumasa
Y
Kuzuhara
Shigeki
S
Honma
Taku
T
Mochizuki
Yoko
Y
Mizutani
Tomohiko
T
Yamada
Satoshi
S
Toi
Sono
S
Sasaki
Shoichi
S
Iwata
Makoto
M
Hirano
Asao
A
Yamamoto
Tomoko
T
Kato
Yoichiro
Y
Sawada
Tatsuo
T
Kobayashi
Makio
M
D000328:Adult; D000368:Aged; D000447:Aldehydes / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D000447:Aldehydes; C000606290:SOD1 protein, human; C012796:2-butenal; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1