Spinocerebellar ataxias (SCAs) are autosomal dominant neurodegenerative disorders that show progressive cerebellar ataxia, often associated with various phenotypes of neurological dysfunction, such as ocular movement disturbances, pyramidal tract or extrapyramidal signs, and peripheral neuropathy. Twenty-six causative genes of SCAs have been described to date,¹ some of which have been identified by exome or whole-genome sequencing in combination with linkage analysis.^2-6 However, causative mutations in a significant number of families with SCA still remain to be identified.

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease caused by a small polyglutamine (polyQ) expansion (control: 4–20Q; SCA6: 20–33Q) in the carboxyl(C)-terminal cytoplasmic domain of the α_1A voltage-dependent calcium channel (Ca_v2.1). Although a 75–85-kDa Ca_v2.1 C-terminal fragment (CTF) is toxic in cultured cells, its existence in human brains and its role in SCA6 pathogenesis remains unknown. Here, we investigated whether the small polyQ expansion alters the expression pattern and intracellular distribution of Ca_v2.1 in human SCA6 brains. New antibodies against the Ca_v2.1 C-terminus were used in immunoblotting and immunohistochemistry. In the cerebella of six control individuals, the CTF was detected in sucrose- and SDS-soluble cytosolic fractions; in the cerebella of two SCA6 patients, it was additionally detected in SDS-insoluble cytosolic and sucrose-soluble nuclear fractions. In contrast, however, the CTF was not detected either in the nuclear fraction or in the SDS-insoluble cytosolic fraction of SCA6 extracerebellar tissues, indicating that the CTF being insoluble in the cytoplasm or mislocalized to the nucleus only in the SCA6 cerebellum. Immunohistochemistry revealed abundant aggregates in cell bodies and dendrites of SCA6 Purkinje cells (seven patients) but not in controls (n = 6). Recombinant CTF with a small polyQ expansion (rCTF-Q28) aggregated in cultured PC12 cells, but neither rCTF-Q13 (normal-length polyQ) nor full-length Ca_v2.1 with Q28 did. We conclude that SCA6 pathogenesis may be associated with the CTF, normally found in the cytoplasm, being aggregated in the cytoplasm and additionally distributed in the nucleus.

Spinocerebellar ataxia type 31 (SCA31) was recently discovered to be caused by 2.5- to 3.8-kb-long complex pentanucleotide repeats containing (TGGAA)n, (TAGAA)n, and (TAAAA)n in an intronic region shared by 2 different genes, BEAN (brain expressed, associated with Nedd4) and TK2 (thymidine kinase 2), in chromosome 16q22.1.1,2 Among the 3 pentanucleotide repeats, (TGGAA)n was the only one in which large repeats segregated with the phenotype, suggesting its importance in pathogenesis.2 SCA31 is considered one of a growing number of neuromuscular diseases with RNA-mediated gain-of-function mechanism such as myotonic dystrophies type 1 and 2, SCA8, SCA10, and fragile X–tremor ataxia syndrome.3 While SCA31 is one of the most common SCAs in Japan, it is not known whether it is prevalent in Caucasians. In this study, we directly tested the SCA31 mutation in large European cohorts of SCA families. ### Methods. French and German cohorts of SCA index patients without known mutations were analyzed. The French cohort (n = 271 patients) was collected through a national ataxia network, and the German cohort (n = 49 patients) was collected at the Ludwig-Maximilians-University Munich, Germany. Healthy controls comprising 285 French and 303 German individuals were also tested. The SCA31 locus and its nearby markers were analyzed as previously described.2 #### Standard protocol approvals, registrations, and patient consents. This study was approved by the respective institutional review boards. ### Results. One out of 49 German and 31 out of 271 French SCA index patients carried abnormal expansions (figure,A). Two of these patients carried expansions homozygously. DNA sequencing revealed that the expansions were located at the same position as in Japanese …