Spinocerebellar ataxia type 6 (SCA6) and 31 (SCA31) exhibit similar clinical and radiological features and have traditionally been distinguishable only through genetic testing. We focused on iron deposition in the cerebellar dentate nucleus (DN) to differentiate these diseases, referencing corresponding pathological findings. Using quantitative susceptibility mapping (QSM), DN susceptibility was measured in 32 patients with SCA6, 31 with SCA31, and 37 controls, and the values were compared among groups. Correlations between susceptibility and disease duration or Scale for the Assessment and Rating of Ataxia (SARA) scores were also evaluated. In separate autopsy cases, Berlin blue and anti-ferritin immunostaining were performed on the DN in five SCA6 cases, one SCA31 case, and three controls. Susceptibility was significantly lower in patients with SCA6 than in those with SCA31 or controls. In SCA6, susceptibility inversely correlated with disease duration, whereas no such correlations were observed in SCA31. In contrast, no significant correlation was noted between susceptibility and SARA scores in either SCA6 or SCA31. Pathological findings showed absent ferritin staining in SCA6, strong staining in controls, and intermediate staining in SCA31. Berlin blue staining was negative in all groups. Reduced DN susceptibility in SCA6 reflects ferritin loss, distinguishing it from SCA31. Assessing DN susceptibility using QSM or SWI may provide useful imaging markers to complement the diagnosis of SCA6 and SCA31.

The expansion of specific repeat sequences causes dozens of heritable neuromuscular diseases, where expanded repeat RNAs play key roles in the pathogenic mechanism. Although the formation of RNA foci has been identified as a common hallmark of repeat diseases, their properties, dynamics, and mechanisms underlying toxicity remain elusive. Here, we demonstrate a novel strategy for the optical control of UGGAA repeat RNA foci, a pathological hallmark of spinocerebellar ataxia type 31 (SCA31), based on the modulation of RNA-RNA interactions by a photoswitchable RNA-binding ligand, NCTA. In the presence of NCTA, UV irradiation induced the growth of UGGAA repeat RNA foci in cells. Subsequent visible light irradiation dissolved the structure into the original smaller RNA foci. Reversible photoisomerization between E- and Z-NCTA is responsible for the photocontrol of RNA foci, where Z-NCTA stabilizes the association between UGGAAs. These changes were accompanied by alterations in the composition of RNA-binding proteins within the RNA foci, suggesting that NCTA modulates their properties and functions by remodeling RNA foci. Our photocontrol system will be useful for investigating, manipulating and regulating dynamic structures containing RNA scaffolds, including disease-related repeat RNA foci and membraneless ribonucleoprotein organelles.

The pathological processes in the early stages of multiple system atrophy (MSA) are still incompletely understood. Moreover, early-stage MSA is difficult to diagnose. We investigated the monoamine oxidase-B positron emission tomography findings with an aim to characterize degeneration in the early stages of MSA. Positron emission tomography using [18F]THK5351 was performed on three patients with relatively early stages of MSA: two with cerebellar-type MSA and one with parkinsonian-type MSA. The findings were compared with nine patients with other parkinsonian disorders (Lewy body disease, progressive supranuclear palsy, or spinocerebellar ataxia type 31) and six control subjects (Alzheimer disease or normal aging). Uptake of [18F]THK5351 in the middle cerebellar peduncles was distinctly higher in all three patients with MSA than in patients with other parkinsonian disorders or control subjects (both p < 0.001; unpaired t-tests). The results of the presented patients suggest the potential diagnostic utility of [18F]THK5351 imaging and may help to clarify the preclinical pathology of the middle cerebellar peduncle in MSA.

The naphthyridine carbamate dimer (NCD) is a small molecule that recognizes disease-related RNA containing UGGAA repeats associated with spinocerebellar ataxia type 31 (SCA 31) and alleviates the disease phenotype in vitro and in vivo. In this study, we use X-ray crystallography to elucidate the mode of NCD binding in detail. We determine the crystal structures of the RNA-NCD complex and a structure of unliganded RNA. The NCD interacts differently than in previously reported nuclear magnetic resonance structure, forming pseudo-canonical base pairs with guanosine residues located on the same RNA strand. Furthermore, in one of the complexes, the ligand is located between symmetry-related RNA molecules, exhibiting a molecular glue characteristics in crystal lattice formation. The comparison of RNA-NCD and ligand-free models allows the identification of structural changes in RNA upon ligand binding from A-form to Z-RNA-like form. These observations extend our understanding of the interactions between RNA and small compounds and can be useful as a reference model in the development of bioinformatics tools for RNA-ligand structure predictions.

Spinocerebellar ataxia type 31 (SCA31) is an autosomal dominant disease, classified amongst pure cerebellar ataxias (ADCA type 3). While SCA31 is the third most prevalent autosomal dominant ataxia in Japan, it is extremely rare in other countries. A literature review was conducted on PubMed, where we included all case reports and studies describing the clinical presentation of original SCA31 cases. The clinical and radiological features of 374 patients issued from 25 studies were collected. This review revealed that the average age of onset was 59.1 ± 3.3 years, with symptoms of slowly progressing ataxia and dysarthria. Other common clinical features were oculomotor dysfunction (38.8%), dysphagia (22.1%), hypoacousia (23.3%), vibratory hypoesthesia (24.3%), and dysreflexia (41.6%). Unfrequently, abnormal movements (7.4%), extrapyramidal symptoms (4.5%) and cognitive impairment (6.9%) may be observed. Upon radiological examination, clinicians can expect a high prevalence of cerebellar atrophy (78.7%), occasionally accompanied by brainstem (9.1%) and cortical (9.1%) atrophy. Although SCA31 is described as a slowly progressive pure cerebellar syndrome characterized by cerebellar signs such as ataxia, dysarthria and oculomotor dysfunction, this study evaluated a high prevalence of extracerebellar manifestations. Extracerebellar signs were observed in 52.5% of patients, primarily consisting of dysreflexia, vibratory hypoesthesia and hypoacousia. Nonetheless, we must consider the old age and longstanding disease course of patients as a confounding factor for extracerebellar sign development, as some may not be directly attributable to SCA31. Clinicians should consider SCA31 in patients with a hereditary, pure cerebellar syndrome and in patients with extracerebellar signs.