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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2026-05-23 | Rad23b exacerbates pathological aggregates through disrupting proteasome functions in Spinocerebellar ataxia type 3.
Spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia globally, caused by expanded CAG repeats in the ATXN3 gene and consequent pathogenic accumulation of mutant ATXN3 (mATXN3) aggregates. The formation of these aggregates perturbs neuronal functions and leads to progressive neurodegeneration, yet the molecular mechanisms controlling mATXN3 proteostasis remain incompletely understood. Here, we identify RAD23 homolog B (Rad23b), a ubiquitin-binding shuttle factor, as a potential regulator of mATXN3 aggregates and toxicity upon high throughput proteomic analysis. Functional assays reveal that Rad23b overexpression enhances, while Rad23b knockdown or knockout reduces, mATXN3 aggregates and neuronal cell death. Mechanistically, Rad23b directly interacts with mATXN3, promotes its ubiquitination, and facilitates its delivery to the proteasome. Paradoxically, Rad23b disrupts proteasome catalytic activity, preventing mATXN3 degradation and exacerbating aggregate formation. Immunohistochemical analysis in SCA3 transgenic mice confirms colocalization of Rad23b with mATXN3 aggregates in cerebellar neurons. These findings highlight Rad23b as a crucial modulator of mATXN3 proteostasis, and imply Rad23b as a potential therapeutic target in SCA3.
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2026-05-08 | Role of nuclear transport receptor KPNB1 in the pathophysiology of spinocerebellar ataxia type 3
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is the most common form of autosomal dominant hereditary ataxias and characterized by a pathological expansion of the polyglutamine (polyQ) tract within the ataxin-3 protein. Ataxin- 3 is mainly a cytoplasmic protein, although polyQ-expanded ataxin-3 accumulates in the nucleus of affected neurons and forms intranuclear aggregates, leading to neurotoxicity and cell death. Unravelling the underlying mechanisms in the nuclear localization of polyQ- expanded ataxin-3 and its involvement in neurotoxicity can provide insight into the pathogenesis of this disease and the development of novel therapeutic strategies. In this respect, investigation of the nucleocytoplasmic transport machinery and its implication for the pathogenesis of SCA3 and other polyQ diseases has gathered attention. Our lab has previously indicated the critical importance of karyopherin α-3 (KPNA3), a nuclear transport receptor, in the nuclear transport of ataxin-3 and its implication in the pathogenesis of SCA3. Since KPNA3 functions as an adaptor protein for karyopherin β-1 (KPNB1) in the nuclear transport of protein cargos, we aimed to explore the role of KPNB1 in the pathogenesis of SCA3 as well. Here, we report on SCA3 cell model-based analysis of the nuclear transport receptor KPNB1 and its implications for the pathogenesis of SCA3. We figured out that KPNB1 interacts directly with both wild-type and polyQ-expanded ataxin-3. However, modulating KPNB1 levels did not change the subcellular distribution of ataxin-3. Interestingly, KPNB1 overexpression reduced protein levels and aggregation of ataxin-3 and promoted its cleavage, whereas its knockdown and pharmacological inhibition led to an increase in soluble and insoluble levels of ataxin-3. Our data revealed that modulation of ataxin-3 was apparently based on protein fragmentation, independent of the classical SCA3-associated proteolytic pathways. Label-free quantitative proteomics and knockdown experiments indicated mitochondrial protease CLPP as a potential mediator of the ataxin-3-degrading effect induced by KPNB1 overexpression. We confirmed a reduction of KPNB1 protein levels in SCA3 by analyzing two SCA3 transgenic mouse models and induced pluripotent stem cells (iPSCs) derived from SCA3 patients. Our findings suggested a yet undescribed regulatory function of KPNB1 in modulating ataxin-3, thereby highlighting a new potential target of therapeutic value for SCA3.
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2026-04-30 | Behavioral and Personality Changes as the First Manifestation of Spinocerebellar Ataxia Type 2.
Background. Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the ATXN2 gene. Although classically characterized by progressive cerebellar ataxia and oculomotor abnormalities, increasing evidence indicates that SCA2 is a multisystem disorder with prominent cognitive, behavioral, and psychiatric manifestations. These non-motor symptoms may precede overt motor signs, leading to diagnostic challenges and misdiagnosis as primary psychiatric conditions. Case Presentation. We report the case of a 59-year-old man with a several-year history of progressive behavioral and emotional dysregulation, initially diagnosed as a personality disorder. Prominent features included irritability, impulsivity, disinhibition, hypersexuality, altered eating behavior, and recurrent self-endangering suicidal gestures, with relatively preserved functional autonomy. Neurological examination revealed subtle cerebellar signs. Neuropsychological assessment showed impaired verbal memory with preserved recognition and borderline attentional–executive deficits, consistent with cerebello–frontal dysfunction. Brain magnetic resonance imaging (MRI) demonstrated moderate-to-severe cerebellar and brainstem atrophy, while dopamine transporter SPECT revealed severe bilateral presynaptic dopaminergic denervation. Cerebrospinal fluid biomarkers excluded Alzheimer’s disease. Genetic testing confirmed SCA2 with 38 CAG repeats in ATXN2. Conclusions. This case illustrates an atypical presentation of SCA2 in which behavioral and psychiatric symptoms preceded motor manifestations by several years. Recognition of such presentations is crucial to avoid misdiagnosis, reduce diagnostic delay, and enable timely genetic counselling and multidisciplinary management, reinforcing the concept of SCA2 as a multisystem neurodegenerative disorder.
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2026-04-29 | Disease-associated mutations impact DNMT1 function through dynamic allosteric effects and solvent exposure
The inputs and scripts for MD simulations of the WT DNMT1 and its variants associated with autosomal dominant cerebellar ataxia–deafness and neuropathy (ADCA-DN) and hereditary sensory and autonomic neuropathy type 1E (HSAN1E).
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