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.

Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons.

We describe a new family with adult onset amyotrophic lateral sclerosis (FALS), in which the disease was characterized clinically by relatively rapid progression of bulbar symptoms. Gene analysis of Cu/Zn superoxide dismutase (SOD1) performed in one patient showed no mutations. Autopsy of another patient demonstrated degenerative changes restricted to the upper and lower motor neuron systems; no evident changes were observed in the posterior column, Clarke's column or spinocerebellar tracts. The presence of Bunina bodies and ubiquitin-positive skein-like inclusions in the lower motor neuron was of considerable interest. Cases of FALS with such pathological features are quite rare in the literature. Identification of the gene responsible for the disease is desirable in order to shed further light on the molecular pathology of not only familial, but also sporadic, ALS.

Familial amyotrophic lateral sclerosis with bulbar onset and a novel Asp101Tyr Cu/Zn superoxide dismutase gene mutation.

We describe a patient with familial amyotrophic lateral sclerosis (FALS) in whom we identified a novel missense mutation in exon 4 (Asp101Tyr) of the Cu/Zn superoxide dismutase (SOD1) gene. The disease started with a bulbar symptom (rapidly progressive hoarseness) and at autopsy showed degenerative changes restricted to the upper and lower motor neuron systems (more strictly, with lower motor predominance, showing the most severe degeneration in the nucleus ambiguus). Occasional intracytoplasmic Lewy-body-like hyaline inclusions that were immunoreactive for ubiquitin and SOD1, but immunonegative for neurofilament protein, were found in the lower motor neurons. This is the first report of hoarseness as the initial manifestation of FALS. This SOD1 gene mutation may be associated with a particular clinicopathological phenotype.

[Clinical features and neuropathological findings of familial amyotrophic lateral sclerosis with an H43R mutation in Cu/Zn superoxide dismutase].

We report the clinical and neuropathological features of a Japanese family with familial amyotrophic lateral sclerosis (FALS), whose members have an amino acid substitution of histidine by arginine in Cu/Zn superoxide dismutase. A 58-year-old woman developed muscle weakness in the legs, and died of respiratory insufficiency 7 months after the onset of her weakness. Her family history included 7 patients with FALS over 3 generations. Their pertinent neurological abnormalities consisted primarily of lower motor neuron signs, and their clinical progression was rapid. Autopsy of our patient showed the involvement of the lower and upper motor neuron systems with Lewy body-like hyaline inclusions, in addition to degeneration in the posterior columns, Clarke's nuclei and posterior spinocerebellar tracts. The inclusions reacted with both anti-SOD1 and anti-ubiquitin antibodies. This is the first report of the neuropathological findings of FALS with this mutation.