Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach.

Mutations in Cu,Zn superoxide dismutase (SOD1) are associated with amyotrophic lateral sclerosis (ALS). Among more than 100 ALS-associated SOD1 mutations, premature termination codon (PTC) mutations exclusively occur in exon 5, the last exon of SOD1. The molecular basis of ALS-associated toxicity of the mutant SOD1 is not fully understood. Here, we show that nonsense-mediated mRNA decay (NMD) underlies clearance of mutant mRNA with a PTC in the non-terminal exons. To further define the crucial ALS-associated SOD1 fragments, we designed and tested an exon-fusion approach using an artificial transgene SOD1(T116X) that harbors a PTC in exon 4. We found that the SOD1(T116X) transgene with a fused exon could escape NMD in cellular models. We generated a transgenic mouse model that overexpresses SOD1(T116X). This mouse model developed ALS-like phenotype and pathology. Thus, our data have demonstrated that a 'mini-SOD1' of only 115 amino acids is sufficient to cause ALS. This is the smallest ALS-causing SOD1 molecule currently defined. This proof of principle result suggests that the exon-fusion approach may have potential not only to further define a shorter ALS-associated SOD1 fragment, thus providing a molecular target for designing rational therapy, but also to dissect toxicities of other proteins encoded by genes of multiple exons through a 'gain of function' mechanism.

A Case of Multiple Sclerosis with Sick Sinus Syndrome and Postural Orthostatic Tachycardia Syndrome / The Japanese Journal of Rehabilitation Medicine

A 19-year-old girl was admitted to our hospital with nausea, vomiting, hiccups, constipation and syncope. After hiccups or vomiting sinus arrest developed and lasted more than 5-8 seconds. She lost consciousness every one hour. Based on an electrocardiographic diagnosis of sick sinus syndrome (SSS), a temporary pacemaker was implanted. The next day, although her syncope and bradycardia disappeared, she had orthostatic tachycardia of over 120 beats/minute and swelling of the legs, which led to a diagnosis of postural orthostatic tachycardia syndrome (POTS). Neurologically, she showed the right-sided tongue deviation and parasympathetic system disorders revealed by coefficient of variation of R-R interval (CV_R-R), the Achner eye-ball pressure test, the valsalva ratio, and the head-up-tilt test. Brain MRI disclosed a small hyperintense lesion on a T2-weighted image with gadolinium enhancement in the right dorsal medulla including the hypoglottis nucleus and the posterior nucleus of vagus. After steroid pulse therapy (methyl prednisolone 1 g/day×3 days, 5 times) was administered, this lesion became smaller and finally disappeared. Before the lesion disappeared, she was able to begin rehabilitation by wearing elastic stockings and treatment with midodrine hydrochloride. The following year, she developed other MRI-proven brain lesions, suggestive of demyelination. Such a spinal and temporal distribution of lesions led to a diagnosis of multiple sclerosis (MS). A case of POTS caused by MS has not been reported previously, however, MS often affects the medullary paraventricular regions associated with autonomic failures. Autonomic failures often prevent patients from experiencing early rehabilitations. We should promptly give symptomatic treatment against autonomic failures, which leads to good patient recovery not only in patient vitality but also functionality.