Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease characterized by progressive ataxia and degeneration of specific neuronal populations, including Purkinje cells (PCs) in the cerebellum. Previous studies have demonstrated a critical role for various evolutionarily conserved signaling pathways in cerebellar patterning, such as the Wnt-β-catenin pathway; however, the roles of these pathways in adult cerebellar function and cerebellar neurodegeneration are largely unknown. In this study, we found that Wnt-β-catenin signaling activity was progressively enhanced in multiple cell types in the adult SCA1 mouse cerebellum, and that activation of this signaling occurs in an ataxin-1 polyglutamine (polyQ) expansion-dependent manner. Genetic manipulation of the Wnt-β-catenin signaling pathway in specific cerebellar cell populations revealed that activation of Wnt-β-catenin signaling in PCs alone was not sufficient to induce SCA1-like phenotypes, while its activation in astrocytes, including Bergmann glia (BG), resulted in gliosis and disrupted BG localization, which was replicated in SCA1 mouse models. Our studies identify a mechanism in which polyQ-expanded ataxin-1 positively regulates Wnt-β-catenin signaling and demonstrate that different cell types have distinct responses to the enhanced Wnt-β-catenin signaling in the SCA1 cerebellum, underscoring an important role of BG in SCA1 pathogenesis.

The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is known to lead to the progressive degeneration of specific neuronal populations, including cerebellar Purkinje cells (PCs), brainstem cranial nerve nuclei and inferior olive nuclei, and spinocerebellar tracts. The disease-causing protein ataxin-1 is fairly ubiquitously expressed throughout the brain and spinal cord, but most studies have primarily focused on the role of ataxin-1 in the cerebellum and brainstem. Therefore, the functions of ataxin-1 and the effects of SCA1 mutations in other brain regions including the cortex are not well-known. Here, we characterized pathology in the motor cortex of a SCA1 mouse model and performed RNA sequencing in this brain region to investigate the impact of mutant ataxin-1 towards transcriptomic alterations. We identified progressive cortical pathology and significant transcriptomic changes in the motor cortex of a SCA1 mouse model. We also identified progressive, region-specific, colocalization of p62 protein with mutant ataxin-1 aggregates in broad brain regions, but not the cerebellum or brainstem. A cross-regional comparison of the SCA1 cortical and cerebellar transcriptomic changes identified both common and unique gene expression changes between the two regions, including shared synaptic dysfunction and region-specific kinase regulation. These findings suggest that the cortex is progressively impacted via both shared and region-specific mechanisms in SCA1.

Coronavirus disease 2019 has posed an enormous global health and economic burden. To date, 324 million confirmed cases and over 5.5 million deaths have been reported. Several studies have reported comorbidities and coinfections associated with complicated and serious COVID-19 infections. Data from retrospective, prospective, case series, and case reports from various geographical locations were assessed, which included ~ 2300 COVID-19 patients with varying comorbidities and coinfection. We report that Enterobacterales with Staphylococcus aureus was the most while Mycoplasma pneumoniae was the least prevalent coinfection in COVID-19 patients with a comorbidity. In this order, hypertension, diabetes, cardiovascular disease, and pulmonary disease were the prevalent comorbidities observed in COVID-19 patients. There was a statistically significant difference in the prevalent comorbidities observed in patients coinfected with Staphylococcus aureus and COVID-19 and a statistically non-significant difference in the prevalent comorbidities in patients coinfected with Mycoplasma pneumoniae and COVID-19 as compared to similar infections in non-COVID-19 coinfection. We report a significant difference in the prevalent comorbidities recorded in COVID-19 patients with varying coinfections and varying geographic study regions. Our study provides informative data on the prevalence of comorbidities and coinfections in COVID-19 patients to aid in evidence-based patient management and care.