Human Cerebellum Research Articles

MRI morphometry of the anterior and posterior cerebellar vermis and its relationship to sensorimotor and cognitive functions in children

IntroductionThe human cerebellum emerges as a posterior brain structure integrating neural networks for sensorimotor, cognitive, and emotional processing across the lifespan. Developmental studies of the cerebellar anatomy and function are scant. We examine age-dependent MRI morphometry of the anterior cerebellar vermis, lobules I-V and posterior neocortical lobules VI-VII and their relationship to sensorimotor and cognitive functions. MethodsTypically developing children (TDC; n=38; age 9–15) and healthy adults (HAC; n=31; 18–40) participated in high-resolution MRI. Rigorous anatomically informed morphometry of the vermis lobules I-V and VI-VII and total brain volume (TBV) employed manual segmentation computer-assisted FreeSurfer Image Analysis Program [http://surfer.nmr.mgh.harvard.edu]. The neuropsychological scores (WASI-II) were normalized and related to volumes of anterior, posterior vermis, and TBV. ResultsTBVs were age independent. Volumes of I-V and VI-VII were significantly reduced in TDC. The ratio of VI-VII to I-V (∼60%) was stable across age-groups; I-V correlated with visual-spatial-motor skills; VI-VII with verbal, visual-abstract and FSIQ. ConclusionsIn TDC neither anterior I-V nor posterior VI-VII vermis attained adult volumes. The "inverted U" developmental trajectory of gray matter peaking in adolescence does not explain this finding. The hypothesis of protracted development of oligodendrocyte/myelination is suggested as a contributor to TDC's lower cerebellar vermis volumes.

Pathologically based criteria to distinguish essential tremor from controls: analyses of the human cerebellum.

Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain studies, hindering attempts to develop pathologically based criteria to distinguish essential tremor from control brains. However, an intensive effort to bank essential tremor brains over recent years has resulted in postmortem studies involving >200 brains, which have identified numerous degenerative changes in the essential tremor cerebellar cortex. Although essential tremor and controls have been compared with respect to individual metrics of pathology, there has been no overarching analysis to derive a combination of metrics to distinguish essential tremor from controls. We asked whether there is a constellation of pathological findings that separates essential tremor from controls, and how well that constellation performs. Analyses included 100 essential tremor brains from the essential tremor centralized brain repository and 50 control brains. A standard tissue block from the cerebellar cortex was used to quantify 11 metrics of pathological change. Three supervised classification algorithms were investigated, with data divided into training and validation samples. Using three different algorithms, we illustrate the ability to correctly predict a diagnosis of essential tremor, with sensitivity and specificity >87%, and in the majority of situations, >90%. We also provide a web-based application that uses these metric values, and based on specified cutoffs, determines the likely diagnosis. These analyses set the stage for use of pathologically based criteria to distinguish clinically diagnosed essential tremor cases from controls, at the time of postmortem.

Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion

The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72. Importantly, the transcriptomic consequences of the C9orf72 repeat expansion remain largely unclear. Here, we used short-read RNA sequencing (RNAseq) to profile the cerebellar transcriptome, detecting alterations in patients with a C9orf72 repeat expansion. We focused on the cerebellum, since key C9orf72-related pathologies are abundant in this neuroanatomical region, yet TDP-43 pathology and neuronal loss are minimal. Consistent with previous work, we showed a reduction in the expression of the C9orf72 gene and an elevation in homeobox genes, when comparing patients with the expansion to both patients without the C9orf72 repeat expansion and control subjects. Interestingly, we identified more than 1000 alternative splicing events, including 4 in genes previously associated with ALS and/or FTLD. We also found an increase of cryptic splicing in C9orf72 patients compared to patients without the expansion and controls. Furthermore, we demonstrated that the expression level of select RNA-binding proteins is associated with cryptic splice junction inclusion. Overall, this study explores the presence of widespread transcriptomic changes in the cerebellum, a region not confounded by severe neurodegeneration, in post-mortem tissue from C9orf72 patients.

Pathologically Based Criteria to Distinguish Essential Tremor from Controls: Analyses of the Human Cerebellum (P3-3.002)

Pathologically Based Criteria to Distinguish Essential Tremor from Controls: Analyses of the Human Cerebellum (P3-3.002)

Optimization of Experimental Conditions to Characterize Perineuronal Nets in the Human Cerebellum

During childhood and adolescence, the brain is highly responsive to external stimuli compared to adulthood. Perineuronal nets (PNNs), play a crucial role during this period by reducing neuroplasticity. These mesh-like structures protect and fortify neural connections between cells. Child abuse includes physical, emotional, and sexual abuse and/or neglect1. It is consistently associated with negative mental and physical health outcomes, underscoring the importance of identifying risk and resilience factors for effective prevention of such outcomes. Our laboratory focuses on understanding the cellular and molecular neuroanatomy of major depression and the lasting impact of child abuse (CA) on the brain. However, the impact of CA on PNNs remains relatively unexplored. How does CA influence the brain, potentially contributing to negative outcomes in the future? Samples from post-mortem human brain cerebellum were dissected and then used to perform RNAscope experiments to label glutamatergic, GABAergic, and parvalbumin-positive cells, following a brief IF protocol using Wisteria Floribunda Lectin (WFL) to visualize PNNs. The RNAscope protocol was successfully optimized by the addition of normal donkey serum (NDS), manipulation of incubation time, and WFL concentration. PVALB+ mRNA expression was positively identified in Purkinje cells, molecular layer interneurons, and deep cerebellar nucleus (DCN) neurons. SLC17A7+ mRNA expression was evident in granule cells and excitatory projection DCN neurons. GAD1+ mRNA expression was detected in Purkinje cells and inhibitory DCN neurons. These results provide an experimental protocol for future studies investigating the role of PNNs in the human cerebellum. We propose that CA alters the recruitment of PNNs, influencing circuitry and potentially increasing susceptibility to various mental illnesses, including major depressive disorder (MDD). MDD, also called clinical depression, causes a persistent feeling of sadness and loss of interest. This study aims to optimize fluorescent in situ hybridization (FISH, RNAscope) and immunofluorescence (IF) markers for the localization and phenotyping of PNN-enwrapped neurons in the human cerebellum. This article describes problems we encountered when running experiments and ways to optimize them. As this work is preliminary, it will help develop future protocols for exploring the effects of depression on PNNs and the phenotype of the cells they encircle. Comparing depressed individuals with and without a history of CA with neurologically and psychiatrically healthy controls will allow us to determine whether a history of CA impacts the distribution and density of PNNs.

FRACTAL ANALYSIS OF BRANCHING OF HUMAN CEREBELLAR ARTERIES

Human cerebellum is supplied by three arteries: the superior surface is nourished by the superior cerebellar artery (SCA), while the inferior surface is supplied by the anterior inferior cerebellar artery (AICA) and the posterior inferior cerebellar artery (PICA). Traditionally, the branching pattern of the superfi cial vascular network is subjectively assessed, distinguishing between the trunk, lose or mixed types. Fractal analysis is an objective alternative method.The aim of this study is to investigate the fractal dimension of branching complexity of superfi cial arteries in the human cerebellum and to establish the relationship between the magnitude of the fractal index and the shape of the cerebellum.Material and Methods. A total of 100 cerebellum samples, including the brainstem, were examined. The width, length, and height of the cerebellum were measured. Parameters of cerebellar shape, namely relative width (rW), relative length (rL), and relative height (rH), were determined as the ratios of the square of one linear dimension to the product of the other two. For fractal analysis, 15 cerebellar samples of various shapes (9 from male and 6 from female individuals) were selected. Fractal analysis of digital images of the superior and inferior surfaces of the cerebellum was performed bilaterally using the box-counting method.Results. The range of fractal index values was determined, and intervals corresponding to the mixed (1.54-1.73), trunk (<1.54) and loose (>1.73) branching types were identifi ed. The superior surface predominantly exhibited trunk or mixed branching types, whereas the inferior surface was more characteristic of mixed or loose branching types. The greatest diversity of arterial branching patterns – from the trunk to lose type – is observed in the most numerous group – cerebella of proportional shape, regardless of which shape parameter is analyzed. The branching pattern of superfi cial cerebellar arteries tends towards a loose type in relatively narrow and relatively short cerebella, and conversely towards a trunk type in relatively wide and relatively long cerebella. Conversely, relative height has an opposite eff ect: the branching pattern of superfi cial cerebellar arteries tends towards a loose type as the relative height of the cerebellum increases. Thus, relatively low cerebella typically exhibit a trunk branching pattern (more noticeable on the superior surface), while in relatively high cerebella, the branching pattern tends towards loose (more noticeable on the inferior surface).

Human Cerebellum Gangliosides: A Comprehensive Analysis by Ion Mobility Tandem Mass Spectrometry.

The human cerebellum is an ultraspecialized region of the brain responsible for cognitive functions and movement coordination. The fine mechanisms through which the process of aging impacts such functions are not well understood; therefore, a rigorous exploration of this brain region at the molecular level is deemed necessary. Gangliosides, sialylated glycosphingolipids, highly and specifically expressed in the human central nervous system, represent possible molecular markers of cerebellum development and aging. In this context, for a comprehensive determination of development- and age-specific components, we have conducted here a comparative profiling and structural determination of the gangliosides expressed in fetal cerebellum in two intrauterine developmental stages and aged cerebellum by ion mobility separation (IMS) mass spectrometry (MS) and tandem MS (MS/MS). Due to the high sensitivity and efficiency of separation provided by IMS MS, no less than 551 chemically distinct species were identified, which represents 4.5 times more gangliosides than ever discovered in this brain region. The detailed assessment of fetal vs aged cerebellum gangliosidome showed marked discrepancies not only in the general number of the species expressed, but also in their sialylation patterns, the modifications of the glycan core, and the composition of the ceramides. All of these characteristics are potential markers of cerebellum development and aging. The structural analysis by collision-induced dissociation (CID) documented the occurrence of GD1b (d18:1/18:0) isomer in the fetal cerebellum in the second gestational trimester, with all probability of GQ1b (t18:1/18:0) in the near-term fetus and of GQ1b (d18:1/18:0) in aged cerebellum.

MiR-124-3p and miR-194-5p regulation of the PI3K/AKT pathway via ROR2 in medulloblastoma progression

Medulloblastoma (MB), a prevalent pediatric central nervous system tumor, is influenced by microRNAs (miRNAs) that impact tumor initiation and progression. However, the specific involvement of miRNAs in MB tumorigenesis remains unclear. Using single-cell RNA sequencing, we identified ROR2 expression in normal human fetal cerebellum. Subsequent analyses, including immunofluorescence, quantitative real-time PCR (qRT-PCR), and Western blot, assessed ROR2 expression in MB tissues and cell lines. We investigated miR-124-3p and miR-194-5p and their regulatory role in ROR2 expression through the dual-luciferase reporter, qRT-PCR, and western blot assays. Mechanistic insights were gained through functional assays exploring the impact of miR-124-3p, miR-194-5p, and ROR2 on MB growth in vitro and in vivo. We observed significantly reduced miR-124-3p and miR-194-5p expression and elevated ROR2 expression in MB tissues and cell lines. High ROR2 expression inversely correlated with overall survival in WNT and SHH subgroups of MB patients. Functionally, overexpressing miR-124-3p and miR-194-5p and inhibiting ROR2 suppressed in vitro malignant transformation and in vivo tumorigenicity. Mechanistically, miR-124-3p and miR-194-5p synergistically regulated the ROR2/PI3K/Akt pathway, influencing MB progression. Our findings indicate that miR-124-3p and miR-194-5p function as tumor suppressors, inhibiting MB progression via the ROR2/PI3K/Akt axis, suggesting a key mechanism and therapeutic targets for MB patients.

A multimodal submillimeter MRI atlas of the human cerebellum

The human cerebellum is engaged in a broad array of tasks related to motor coordination, cognition, language, attention, memory, and emotional regulation. A detailed cerebellar atlas can facilitate the investigation of the structural and functional organization of the cerebellum. However, existing cerebellar atlases are typically limited to a single imaging modality with insufficient characterization of tissue properties. Here, we introduce a multifaceted cerebellar atlas based on high-resolution multimodal MRI, facilitating the understanding of the neurodevelopment and neurodegeneration of the cerebellum based on cortical morphology, tissue microstructure, and intra-cerebellar and cerebello-cerebral connectivity.

Single-cell multi-omics analysis of lineage development and spatial organization in the human fetal cerebellum

Human cerebellum encompasses numerous neurons, exhibiting a distinct developmental paradigm from cerebrum. Here we conducted scRNA-seq, scATAC-seq and spatial transcriptomic analyses of fetal samples from gestational week (GW) 13 to 18 to explore the emergence of cellular diversity and developmental programs in the developing human cerebellum. We identified transitory granule cell progenitors that are conserved across species. Special patterns in both granule cells and Purkinje cells were dissected multidimensionally. Species-specific gene expression patterns of cerebellar lobes were characterized and we found that PARM1 exhibited inconsistent distribution in human and mouse granule cells. A novel cluster of potential neuroepithelium at the rhombic lip was identified. We also resolved various subtypes of Purkinje cells and unipolar brush cells and revealed gene regulatory networks controlling their diversification. Therefore, our study offers a valuable multi-omics landscape of human fetal cerebellum and advances our understanding of development and spatial organization of human cerebellum.

The Role of the Human Cerebellum for Learning from and Processing of External Feedback in Non-Motor Learning: A Systematic Review

This review aimed to systematically identify and comprehensively review the role of the cerebellum in performance monitoring, focusing on learning from and on processing of external feedback in non-motor learning. While 1078 articles were screened for eligibility, ultimately 36 studies were included in which external feedback was delivered in cognitive tasks and which referenced the cerebellum. These included studies in patient populations with cerebellar damage and studies in healthy subjects applying neuroimaging. Learning performance in patients with different cerebellar diseases was heterogeneous, with only about half of all patients showing alterations. One patient study using EEG demonstrated that damage to the cerebellum was associated with altered neural processing of external feedback. Studies assessing brain activity with task-based fMRI or PET and one resting-state functional imaging study that investigated connectivity changes following feedback-based learning in healthy participants revealed involvement particularly of lateral and posterior cerebellar regions in processing of and learning from external feedback. Cerebellar involvement was found at different stages, e.g., during feedback anticipation and following the onset of the feedback stimuli, substantiating the cerebellum’s relevance for different aspects of performance monitoring such as feedback prediction. Future research will need to further elucidate precisely how, where, and when the cerebellum modulates the prediction and processing of external feedback information, which cerebellar subregions are particularly relevant, and to what extent cerebellar diseases alter these processes.

Identification and Analysis of ZIC-Related Genes in Cerebellum of Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with significant genetic heterogeneity. The ZIC gene family can regulate neurodevelopment, especially in the cerebellum, and has been implicated in ASD-like behaviors in mice. We performed bioinformatic analysis to identify the ZIC gene family in the ASD cerebellum. We explored the roles of ZIC family genes in ASD by investigating (i) the association of ZIC genes with ASD risk genes from the Simons Foundation Autism Research Initiative (SFARI) database and ZIC genes in the brain regions of the Human Protein Atlas (HPA) database; (ii) co-expressed gene networks of genes positively and negatively correlated with ZIC1, ZIC2, and ZIC3, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and receiver operating characteristic (ROC) curve analysis of genes in these networks; and (iii) the relationship between ZIC1, ZIC2, ZIC3, and their related genes with cerebellar immune cells and stromal cells in ASD patients. (i) ZIC1, ZIC2, and ZIC3 were associated with neurodevelopmental disorders and risk genes related to ASD in the human cerebellum and (ii) ZIC1, ZIC2, and ZIC3 were highly expressed in the cerebellum, which may play a pathogenic role by affecting neuronal development and the cerebellar internal environment in patients with ASD, including immune cells, astrocytes, and endothelial cells. (iii) OLFM3, SLC27A4, GRB2, TMED1, NR2F1, and STRBP are closely related to ZIC1, ZIC2, and ZIC3 in ASD cerebellum and have good diagnostic accuracy. (iv) ASD mice in the maternal immune activation model demonstrated that Zic3 and Nr2f1 levels were decreased in the immune-activated cerebellum. Our study supports the role of ZIC1, ZIC2, and ZIC3 in ASD pathogenesis and provides potential targets for early and accurate prediction of ASD.

An improved organoid model of the human cerebellum.

An improved organoid model of the human cerebellum.

Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum

Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington’s disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic excision of CAG slip-outs by FAN1. Our data support a model in which CAG expansions are necessary but may not be sufficient for cell death and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity.

Human cerebellar organoids with functional Purkinje cells

Research on human cerebellar development and disease has been hampered by the need for a human cell-based system that recapitulates the human cerebellum's cellular diversity and functional features. Here, we report a human organoid model (human cerebellar organoids [hCerOs]) capable of developing the complex cellular diversity of the fetal cerebellum, including a human-specific rhombic lip progenitor population that have never been generated invitro prior to this study. 2-month-old hCerOs form distinct cytoarchitectural features, including laminar organized layering, and create functional connections between inhibitory and excitatory neurons that display coordinated network activity. Long-term culture of hCerOs allows healthy survival and maturation of Purkinje cells that display molecular and electrophysiological hallmarks of their invivo counterparts, addressing a long-standing challenge in the field. This study therefore provides a physiologically relevant, all-human model system to elucidate the cell-type-specific mechanisms governing cerebellar development and disease.

Improving cellular diversity in human cerebellar organoids

The developing human cerebellum has a greater diversity of progenitor types than that of the mouse, necessitating a human-based model for studying cerebellar development and disease. Atamian etal.1 developed a 3D organoid model of cerebellar development, which recapitulates many cell types found in the developing human cerebellum, including Purkinje-neuron-like cells.

A method of evaluation of the shape of the human cerebellum: MRI study

The variability of shape of an organ is one of the manifestations of its individual anatomical variability. Magnetic resonance imaging and other modern neurovisualization methods allow for in vivo determination of morphological characteristics of organs, considering their natural positioning. The aim of this study is to develop a method of evaluation of the shape of the human cerebellum based on the results of MR imaging morphometry. MR images of the brain were obtained from 30 subjects (15 male and 15 female aged between 20 and 40 years) without apparent brain pathology. MRI was performed using a 1.5 T MRI machine (Siemens Magnetom Symphony, Munich, Germany). The width of the cerebellum was determined in axial (Wax) and coronal (Wcor) planes, the length was determined in axial (Lax) and sagittal (Lsag) planes, the height was determined in coronal (Hcor) and sagittal (Hsag) planes. It was observed that the width of the cerebellum is determined almost equally in two different planes, the greater disparity is noted in the measurements of length and the maximum difference in values was found in the measurements of height. A moderate and statistically significant linear relationship was discovered between the variables Wax and Lax (r=0.48; p<0.01), as well as between Wcor and Hcor (r=0.39; p<0.05). Variability in the values of paired linear dimensions measured in a single plane and the absence of a functional relationship between them lead to variability in their ratios, or shape factors (Wax / Lax, Wcor / Hcor, Lsag / Hsag). These shape factors, in turn, influence the shape of intracerebellar structures, primarily the cerebellar nuclei. To evaluate the overall shape of the cerebellum, the following parameters have been proposed, which describe the relationships between one linear dimension of the cerebellum to the other two: relative width of the cerebellum (Wr=(Wax×Wcor) / (Lax×Hcor)), relative length of the cerebellum (Lr=(Lax×Lsag) / (Wax×Hsag)), and relative height of the cerebellum (Hr=(Hcor×Hsag) / (Wcor×Lsag)). Further analysis of these parameters defines which of the linear dimensions has a greater influence on the shape of the cerebellum, determining its structural features, such as the shape of its lobules, the course of its fissures, and the three-dimensional organization of its nuclei, among others. In vivo evaluation of cerebellar shape will facilitate improvements in the diagnosis of cerebellar disorders using MRI and will be valuable in conducting neuromorphological research studies.

The Reduced Gray Matter Volume and Functional Connectivity of the Cerebellum in Type 2 Diabetes Mellitus with High Insulin Resistance

Introduction: Insulin resistance is widely thought to be a critical feature in type 2 diabetes mellitus (T2DM), and there is significant evidence indicating a higher abundance of insulin receptors in the human cerebellum than cerebrum. However, the specific structural or functional changes in the cerebellum related to T2DM remain unclear, and the association between cerebellar alterations, insulin resistance, cognition, and emotion is yet to be determined. Methods: We investigated neuropsychological performance, and structural and functional changes in specific cerebellar subregions in 43 T2DM patients with high insulin resistance (T2DM-highIR), 72 T2DM patients with low insulin resistance (T2DM-lowIR), and 50 controls. Furthermore, the correlation and stepwise multiple linear regression analysis were performed. Results: Compared to the controls, T2DM exhibited lower cognitive scores and higher depressive/anxious scores. Furthermore, T2DM-highIR patients showed reduced gray matter volume (GMV) in the right cerebellar lobules VIIb, Crus I/II, and T2DM showed reduced GMV in left lobules I–IV compared to controls. Additionally, functional connectivity decrease was observed between the right lobules I–V and orbital part of the superior frontal gyrus in T2DM-highIR compared to both T2DM-lowIR and controls. Notably, there were negative correlations between the GMV of the lobules VIIb, Crus I/II, and updated homeostatic model assessment of insulin resistance, and positive correlation with executive/visuospatial performance in T2DM patients. Conclusions: These results suggest that the cerebellar lobules VIIb, Crus I/II, represent vulnerable brain regions in the context of insulin resistance. Overall, this study offers new insights into the neuropathophysiological mechanisms of brain impairment in patients with T2DM.

Multi-resolution X-ray phase-contrast and dark-field tomography of human cerebellum with near-field speckles.

In this study, we use synchrotron-based multi-modal X-ray tomography to examine human cerebellar tissue in three dimensions at two levels of spatial resolution (2.3 µm and 11.9 µm). We show that speckle-based imaging (SBI) produces results that are comparable to propagation-based imaging (PBI), a well-established phase-sensitive imaging method. The different SBI signals provide complementary information, which improves tissue differentiation. In particular, the dark-field signal aids in distinguishing tissues with similar average electron density but different microstructural variations. The setup's high resolution and the imaging technique's excellent phase sensitivity enabled the identification of different cellular layers and additionally, different cell types within these layers. We also correlated this high-resolution phase-contrast information with measured dark-field signal levels. These findings demonstrate the viability of SBI and the potential benefit of the dark-field modality for virtual histology of brain tissue.

Recent topics of spinocerebellar ataxia type 31

AbstractSpinocerebellar ataxia type 31 (SCA31) is an autosomal‐dominant neurodegenerative condition caused by a 2.5–3.8 kb‐long complex repeat containing (TGGAA/TTCCA)n in an intron shared by two genes called brain expressed, associated with Nedd4 (BEAN1) and thymidine kinase 2 (TK2) located in the human chromosome 16q22.1. Since BEAN1 and TK2 are transcribed in mutually opposite directions in human brains, two independently transcribed RNAs containing either (UGGAA)n or (UUCCA)n are likely to associate with the pathogenesis of SCA31. Recently, a minor TK2 mRNA isoform called TK2‐EXT was confirmed to be transcribed in human cerebellum, suggesting that (UUCCA)n is indeed expressed. The level of TK2 mRNA and TK2 protein expression levels was both preserved in SCA31 human cerebellum, suggesting that the expression of (UUCCA)n does not affect the expression of TK2, and hence, the function of TK2 seemed to be preserved. On the other hand, the other penta‐nucleotide RNA repeat (UGGAA)n, expressed through BEAN1 transcription, is likely to conform toxicity through forming abnormal RNA structures called RNA foci in the nucleus of expressing cells. In addition, three proteins TDP‐43, FUS, and hnRNPA2/B1 that commonly have a capacity to bind with (UGGAA)n reduced the number of RNA foci, and ameliorated the phenotype brought by (UGGAA)n in Drosophila. A small compound naphthyridine carbamate dimer that binds to (UGGAA)n dampened the (UGGAA)n toxicity in Drosophila, further supporting the idea that (UGGAA)n expressed by BEAN1 is pathogenic. Therefore, a plausible approach to treat SCA31 may be considered by administering agents with a capacity binding to (UGGAA)n.