2026-06-24 | Supplementary Material for: Downbeat Nystagmus and Saccadic Oscillations in Spinocerebellar Ataxia Type 27B: A 14-Month Follow-Up Case Report
Introduction: Spinocerebellar ataxia type 27B (SCA27B) is a late-onset autosomal dominant cerebellar disorder associated with oculomotor abnormalities, particularly downbeat nystagmus (DBN) and saccadic oscillations such as square-wave jerks (SWJ). Although these features are common, their longitudinal evolution and response to aminopyridine therapy remain insufficiently characterized. Case Presentation: We report a 67-year-old male with genetically confirmed SCA27B. At baseline, he presented with cerebellar ataxia (SARA score 11) and frequent SWJ, while DBN was detectable only during head-shaking. After 12 months, mild clinical progression was observed (SARA 12) with the emergence of spontaneous DBN, which intensified during provocative manoeuvres. Treatment with fampridine (20 mg/day) resulted in clinical improvement after two months, reflected by a reduced SARA score (8) and improved gait, stance, and speech. However, video-oculography showed only minimal changes in DBN and no significant reduction in SWJ frequency. Discussion: This case highlights that DBN in SCA27B may initially be detectable only under provocative conditions before becoming spontaneous. Despite clinical improvement with fampridine, objective oculomotor parameters remained largely unchanged, suggesting a possible dissociation between clinical and oculomotor outcomes. Larger longitudinal studies are needed to clarify these relationships.
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2026-05-28 | Aromatic-Turmerone Analogs Activate Chaperone-Mediated Autophagy and Ameliorate Dendritic Shrinkage in Purkinje Cell Models of Spinocerebellar Ataxia.
We recently demonstrated that aromatic (ar)-turmerone analogs ((E)-5-methyl-1-(p-tolyl)hexa-1,4-dien-3-one [A2] and (E)-1-(4-methoxyphenyl)-5-methylhexa-1,4-dien-3-one [A4]) activate chaperone-mediated autophagy (CMA), a pathway in the autophagy-lysosome protein degradation system, in SH-SY5Y cells. Our previous studies revealed that the impairment of CMA and microautophagy (mA), another autophagy-related pathway, and dendritic shrinkage were observed in primary cultured Purkinje cells (PCs) expressing causal proteins of spinocerebellar ataxia (SCA), an autosomal dominant neurodegenerative disease. In the present study, we first investigated the effects of A2 and A4 on lysosomal protein degradation and dendritic morphology in cerebellar primary cultured PCs. Both compounds enhanced dendritic development and activated CMA in cultured PCs. These effects were significantly suppressed by the inhibitors of nuclear factor erythroid 2-related factor 2 and p38. We next examined the effects of A2 and A4 on PCs expressing several types of SCA-causing proteins (SCA model PCs). Both chemicals ameliorated the dendritic shrinkage and restored the decreased CMA/mA activity in several SCA model PCs. These findings suggest that the ar-turmerone analogs A2 and A4 improve the in vitro phenotype of SCA model PCs through CMA activation, highlighting the therapeutic potential of these analogs for various types of SCAs.
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2026-05-25 | Intermittent Theta-Burst Stimulation (iTBS) Improves Motor Coordination and Modulates Neuroinflammation and Autophagy in SCA3/MJD Mice.
Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disorder characterized by misfolded ataxin-3 aggregation and neuronal intranuclear inclusions. Its primary symptom is progressive ataxia, progressively restricting daily living activities. While repetitive transcranial magnetic stimulation (rTMS) may alleviate symptoms, the effects and mechanisms of specific rTMS paradigms, particularly intermittent and continuous theta burst stimulation (iTBS/cTBS), remain unclear in SCA3. This study therefore aimed to investigate the impacts of iTBS and cTBS on motor coordination, cerebellar neuroinflammation, and autophagy in SCA3 transgenic mice. Thirty 14-week-old SCA3 transgenic mice were randomly divided into sham, cTBS, and iTBS groups. Cerebellar stimulation was delivered at 30% maximum output (600 pulses/session, once daily, 5 days/week for 2 weeks). Motor coordination was assessed via rotarod and CatWalk gait analysis. Pathological changes were evaluated by measuring ataxin-3 protein and ubiquitin-positive inclusions. Cerebellar neuroinflammation was analyzed using Iba-1, CD206, and a cytokine array, while autophagy was assessed via Beclin-1 and LC3B expression. iTBS significantly improved motor coordination in SCA3 mice, reducing rotarod falls (vs. sham P < 0.001, vs. cTBS P < 0.05) and improving gait symmetry (vs. sham P < 0.05) and regularity index (vs. sham P < 0.01, vs. cTBS P < 0.01). It also alleviated cerebellar pathology, lowering ataxin-3 expression (vs. sham P < 0.01, vs. cTBS P < 0.01) and ubiquitin-positive inclusions (vs. sham P < 0.01, vs. cTBS P < 0.05). While both iTBS and cTBS increased Iba-1-positive cells (P < 0.05 and P < 0.05, respectively, vs. sham), only iTBS raised CD206-positive cells (vs. sham P < 0.05) and downregulated pro-inflammatory cytokines. Furthermore, iTBS activated autophagy, enhancing Beclin-1 (vs. sham P < 0.05) and LC3B expression (vs. sham P < 0.0001, vs. cTBS P < 0.001). iTBS improved motor coordination and alleviated core cerebellar pathology in SCA3 mice. This effect may be mediated through the downregulation of cerebellar neuroinflammation and the activation of autophagy. Furthermore, the therapeutic efficacy of iTBS was superior to that of cTBS across multiple dimensions, demonstrating distinct paradigm specificity.
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