2026-07-10 | Immune Activation and Glial Dysfunction in Spinocerebellar Ataxias: From Cerebellar Landscape to Disease-Driven Mechanisms and Immunomodulation.
Spinocerebellar ataxias (SCAs) comprise a clinically and genetically heterogeneous group of autosomal dominant neurodegenerative disorders. Despite the recognized role of specialized cerebellar glia in cerebellar development and dysfunction, immune activation and non-immune glial responses remain understudied in SCAs. This narrative review compiles evidence from cellular, animal, and human models on the cerebellar immune landscape and the specific pathways that drive homeostatic failure and neuroinflammatory cascades across SCA subtypes. Microgliosis emerges consistently-and often early- as a generalized feature across the SCA spectrum, preceding neurodegeneration in several subtypes. Concurrently, reactive astrogliosis extends broadly, reflecting widespread macroglial surveillance and metabolic stress regulation throughout histologically preserved gray matter, with specialized homeostatic failure of Bergmann glia in SCA1, SCA2, and SCA7. Peripheral inflammation, manifests as early as the prodromal stage and correlates with the cognitive-affective deficits in SCA2 and associates with the mutation size in SCA3, positioning it as integral to pathogenesis rather than epiphenomenal. Diverse, partially shared signaling pathways converge on multi-lineage glial breakdown and reciprocal neuroimmune crosstalk. These mechanisms involve NF-κB (SCA1,3,17), cGAS-STING (SCA2), TLR/MyD88 (SCA6), and JNK/c-Jun (SCA1,2,7). This review establishes abnormal reciprocal immune/non-immune glia crosstalk as a core pathogenic principle across SCAs, revealing novel therapeutic opportunities. In fact, targeting convergent signaling nodes such as NF-κB, or JNK pathways, holds disease-modifying potential across multiple subtypes. Future research should prioritize standardized comparative studies, longitudinal analyses linking both inflammation and non-immune glial pathology to clinical progression, and clinical trials evaluating targeted immunomodulatory and glial homeostatic-supportive agents.
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2026-05-25 | 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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