title: Protein-bound crotonaldehyde accumulates in the spinal cord of superoxide dismutase-1 mutation-associated familial amyotrophic lateral sclerosis and its transgenic mouse model.
abstract: 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.
authors.affiliation: Department of Pathology, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan. shibatan@research.twmu.ac.jp
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Shibata
authors.forename: Motoko
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Nakano
authors.forename: Harutoshi
authors.initials: H
authors.lastname: Fujimura
authors.forename: Saburo
authors.initials: S
authors.lastname: Sakoda
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Ihara
authors.forename: Keigo
authors.initials: K
authors.lastname: Nobukuni
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takehisa
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Kuroda
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Kokubo
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuzuhara
authors.forename: Taku
authors.initials: T
authors.lastname: Honma
authors.forename: Yoko
authors.initials: Y
authors.lastname: Mochizuki
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Mizutani
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamada
authors.forename: Sono
authors.initials: S
authors.lastname: Toi
authors.forename: Shoichi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Iwata
authors.forename: Asao
authors.initials: A
authors.lastname: Hirano
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kato
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Sawada
authors.forename: Makio
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: 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
chemical_list: D000447:Aldehydes; C000606290:SOD1 protein, human; C012796:2-butenal; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1