2017 年 34 巻 2 号 p. 107-111
Asidan, which is a nicknamed of spinocerebellar ataxia type 36 (SCA36), is a novel dominant disorder caused by a hexanucleotide GGCCTG repeat expansion in intron 1 of the NOP56 gene. Common symptoms of Asidan patients are truncal ataxia, dysarthria and limb ataxia (a sign of cerebellar ataxia), hyperreflexia and tongue atrophy, fasciculation (a sign of motor neuron disease), cognitive and affective impairment and hearing loss. Therefore, Asidan stands at the crossroads of SCA and motor neuron disease. (GGCCUG)n repeat RNA foci formation was detected in lymphoblastoid cells from Asidan patients by fluorescence in situ hybridization. Double staining and gel–shift assay showed that (GGCCUG)n binds the RNA–binding protein SRSF2, suggesting that Asidan is caused by hexanucleotide repeat expansions through RNA gain of function. Interestingly, G93A–SOD1 transgenic mice, which is a ALS model mouse, show progressive reduction of NOP56 levels in the large motor neurons of spinal cords from the early–symptomatic stage to the end stage of the disease. TDP–43 and FUS protein levels, which participates in RNA processing pathway similar to NOP56, showed a later decrease in the nucleus of large motor neuron at end stage of the disease. These changes were not observed in the primary motor cortex of the cerebrum as well as molecular and granular layers and Purkinje cells in the cerebellum, suggesting a progressive loss of these three nuclear proteins, especially NOP56, and subsequent RNA processing problems including a novel gene relating to ALS (NOP56) under the motor neuron degeneration. Recent reports showed sporadic and familial amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) in the Caucasian population is caused by hexanucleotide GGGGCC repeat expansion in intron 1 of the C9orf72 gene, similar to the genetic mutation in Asidan patients. Since C9orf72 mutation induces neurodegeneration of Purkinje cells, it is possible that a similar genetic pathology for cerebellar ataxia, motor neuron disease signs and cognitive impairment may be at play in both Asidan and ALS/FTD.