Spinocerebellar ataxia type 8 (SCA8) is a member of a group of dominantly inherited, debilitating neurological diseases caused by CAG•CTG expansions for which there are no effective treatments. RAN translation, which was discovered in SCA8, has previously been shown to occur across CAG and CUG expansion transcripts, making treatments for SCA8 potentially relevant to a broad group of diseases, including SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, Huntington's disease, and myotonic dystrophy type 1. In addition, CUG and CAG expansion transcripts have been reported to cause RNA gain-of-function effects. Using SCA8 BAC transgenic mice as a model for CAG•CTG expansion diseases, we now show that metformin improves ambulatory performance using rotarod, DigiGait, and open-field testing. At the molecular level, metformin-treated mice show reduced RAN protein levels and improved splicing, without altering sense or antisense RNA levels. Metformin-treated mice also show decreased neuroinflammation, with reduced astrogliosis and fewer activated microglia. These data provide strong preclinical support for testing metformin in clinical trials for SCA8 and potentially the broader group of CAG•CTG repeat expansion disorders.

Spinocerebellar Ataxia Type 8 (SCA8) is a rare, dominantly inherited neurodegenerative disorder characterized by progressive ataxia and nystagmus, and dysarthria. SCA8 is caused by bidirectional CTG/CAG repeat expansion in the ATXN8OS and ATXN8 gene. Peripheral blood mononuclear cells obtained from a SCA8 patient were successfully transformed into induced pluripotent stem cells (iPSC) (KCGMHi003-A) using Sendai virus. Our approach provided a resource for future pathogenesis study and drug screening of SCA8.

Spinocerebellar ataxia type 8 (SCA8) is a rare neurodegenerative disease that is caused by CAG/CTG repeat expansion in the overlapping ATXN8 and ATXN8OS genes and basically entails slowly progressive cerebellar dysfunction with resultant dysarthria, limb incoordination, and gait instability. Moreover, patients with SCA8 may also exhibit pyramidal and extrapyramidal signs, cognitive decline, and involuntary movements. Although SCA8 is an autosomal dominant inheritance disorder, it sometimes seems to be sporadic because of reduced penetrance. Due to the wide variety of neurological findings and seemingly unclear inheritance pattern, the diagnosis of SCA8 can be difficult in the absence of cerebellar signs or family history. A 62-year-old woman presented with involuntary movements in her right limbs that occurred intermittently for two weeks. Her medical and medication history was unremarkable and she had a paternal grandmother who was diagnosed with Parkinson's disease. Neurological examination revealed right-sided hemichorea without other abnormalities. Head magnetic resonance imaging (MRI) did not reveal acute ischemic or hemorrhagic lesions; instead, it displayed mild cerebellar atrophy. In addition, dopamine transporter-single photon emission computed tomography (DAT-SPECT) detected bilaterally decreased striatal tracer uptake. Although she had no relatives with similar symptoms or SCA, a set of genetic molecular tests for SCA was conducted because she had mild cerebellar atrophy found on MRI. It detected CTA/CTG repeat expansion in the ATXN8OS gene (18/125 repeats; normal range: 15-50). She was diagnosed with SCA8, which was considered the cause for her hemichorea. Oral haloperidol was initiated as symptomatic treatment and it largely resolved her hemichorea. We should remember that patients with SCA8 can present with hemichorea as the sole clinical manifestation. Moreover, DAT-SPECT may detect their nigrostriatal hypofunction even if they do not have clinically apparent parkinsonism.

The genetic etiology of Parkinson's disease (PD) is complex; approximately 10% of patients with PD have various gene mutations that lead to familial forms of the disease. Recent analyses of non-coding repeat regions revealed that many neurodegenerative diseases are associated with pathological expansions. We evaluated the genetic background of non-coding repeat expansions in Japanese patients with PD. We collected blood samples from 203 Japanese patients with PD and analyzed various non-coding repeat genes, including ATXN8OS, RFC1, C9ORF72, NOTCH2NLC, BEAN1/TK2, and NOP56, using PCR-Sanger sequencing, repeat-primed PCR assay, and long-read sequencing. Three patients with PD (1.5%) were found to have heterozygous repeat expansions in ATXN8OS, the gene causative of spinocerebellar ataxia type 8 and is associated with long non-coding RNA. One (0.5%) patient had compound heterozygous repeat expansions (AAGGG and ACAGG) in RFC1, the gene causative of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, which encodes a DNA repair protein. No patient had repeat expansions in C9ORF72, NOTCH2NLC, BEAN1/TK2, or NOP56. All patients with ATXN8OS repeat expansions exhibited typical parkinsonism with relatively rare subjective dysphagia, which was confirmed by videofluoroscopic results. Functional imaging, such as dopamine-transporter single photon emission computed tomography, showed abnormal findings in patients with non-coding repeat expansions. Our findings revealed the importance of non-coding repeat expansions in Japanese patients with PD. This is the first study to show the positive result of non-coding repeat expansions in many patients with PD in Japan.