Koki Kikugawa

Instability of mutant Cu/Zn superoxide dismutase (Ala4Thr) associated with familial amyotrophic lateral sclerosis☆

In about 20-25% of cases of familial amyotrophic lateral sclerosis (FALS) patients have mutations in the Cu/Zn superoxide dismutase (SOD1) gene. The mechanism through which the mutations in the SOD1 gene cause ALS still remain unknown. We performed pulse-chase experiments using a system for the transient expression of human SOD1 in COS7 cells to examine whether the Ala4Thr mutation, which we previously reported, decreases the stability of SOD1. The expression vector (pEF-BOS) carrying the wild-type or mutant (Ala4Thr) human SOD1 cDNA was transfected into COS7 cells, and transiently expressed human SOD1 was then metabolically radiolabeled. Half-lives of the wild-type and the Ala4Thr mutant SOD1 were determined to be 78 h and 18 h, respectively. These results suggest that the Ala4Thr mutation in SOD1 decreases the stability of SOD1 and that this instability may play an important role in the pathogenesis of the degeneration of motor neurons in FALS.

Administration of prosaposin ameliorates spatial learning disturbance and reduces cavity formation following stab wounds in rat brain

The effectiveness of prosaposin as a neurotrophic factor was investigated using rats with bilateral stab wounds, injecting 240 ng per day of prosaposin for 3 days. In Morris water maze task, after 3 weeks postoperation, the stab-wounds rats show significant impairment in acquisition compared with the sham-operated rats. In the transfer test the mean number of crossings of the platform place in stab-wounds was significantly lower than that in sham-operated rats (P < 0.01). The stab-wounds rats treated with prosaposin showed significant improvement (P < 0.05). The cavities following stab wounds in the rats treated with prosaposin were significantly smaller than those in the rats treated with (P < 0.05). Our data support that prosaposin is likely to be a new agent for brain injury.

Familial amyotrophic lateral sclerosis with widespread vacuolation and hyaline inclusions

This report presents a familial amyotrophic lateral sclerosis (FALS) patient with widespread vacuoles and hyaline inclusions strongly immunostained with the anti-superoxide dismutase (SOD1) antibody. The overall pathologic similarity between our non-SOD1-linked FALS patient and transgenic mice expressing a mutated human SOD1 gene suggests that common pathogenetic mechanisms other than an SOD1 mutation exist in the development of these disease.

A missense mutation in the SOD1 gene in patients with amyotrophic lateral sclerosis from the Kii Peninsula and its vicinity, Japan.

ABSTRACTUnusually high incidences of amyotrophic lateral sclerosis (ALS) have been observed in the natives of the Kii Peninsula of Japan as well as the indigenous Chamorro people of Guam. Given the relatively high incidence of familial onset of the disease in the Kii Peninsula, we performed mutational analyses of the SOD1 gene of 23 patients (three familial cases and 20 sporadic cases) with ALS from the Kii Peninsula and its vicinity. In two of the 23 patients, we identified the same missense mutation (substitution of Thr for Ile 113) in exon 4 as a heterozygous state. The Ile113Thr mutation in the SOD1 gene has been identified in some familial as well as sporadic cases with ALS, as a mutation with a low penetrance. This mutation has been reported to be associated with the formation of neurofibrillary tangles in an English family, which is a characteristic feature of ALS in the Kii Peninsula. These results suggest that the Ile113Thr mutation is a characteristic and relatively prevalent mutation in this area.

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 onset in bulbar sign, benign clinical course, and Bunina bodies: a clinical, genetic, and pathological study of a Japanese family

Abstract We report a Japanese family with autosomal dominant adult-onset amyotrophic lateral sclerosis (FALS) with onset in the bulbar musculature, clinically benign course, absence of the Cu/Zn superoxide dismutase-1 (SOD 1) gene mutation, and many Bunina bodies, in addition to involvement of the upper and lower motor neurons. The proband was a Japanese woman who was 66 years old at the time of death. Family history disclosed five patients with FALS over three generations. She developed dysarthria at age 57, followed by dysphagia, muscle weakness of the upper extremities, and difficulty in respiration. She could walk without support until her death. The elder sister of the proband developed dysarthria at age 48 and died at age 58. A genetic study of the nephew of the proband showed the absence of a mutation in the SOD 1 gene. Neuropathological examination of the proband disclosed neuronal loss in the upper and lower motor neurons, and numerous Bunina bodies in the lower motor neurons without Lewy body-like inclusions or ubiquitin-immunoreactive neuronal inclusions. No degeneration of the Clarke’s column, middle root zone of the posterior column, or posterior spinocerebellar tract was present. Review of the literature revealed that only patients with FALS with a long survival period of over 5 years had pathological findings consistent with FALS with posterior column involvement. This study contributes to the elucidation of the clinicopathological heterogeneity of FALS.

Sacsin-related ataxia with neither retinal hypermyelination nor spasticity

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disorder characterized by early-onset spastic ataxia, peripheral neuropathy, and retinal hypermyelination (OMIM 270550).1 Recent reports have revealed the clinical diversity of ARSACS.2 In these patients, either spasticity or retinal hypermyelination has been observed. Here, we report a new nonsense mutation in SACS3 in Japanese siblings with neither retinal hypermyelination nor spasticity.