Generation of a novel immunodeficient mouse model of Mucopolysaccharidosis type IIIA to test human stem cell-based therapies.

Mucopolysaccharidosis Type IIIA (MPSIIIA) is a rare inherited lysosomal storage disease caused by mutations in the SGSH gene. This genetic variation results in the deficiency of the N-sulfoglucosamine sulfohydrolase enzyme, preventing the breakdown of heparan sulfate within lysosomes. The progressive accumulation of partially degraded substrate ultimately leads to brain pathology, for which there is currently no approved treatment. An established MPSIIIA mouse model has proved to be a vital asset to test several brain-targeting strategies. Nonetheless, the assessment of human stem cell-based products, an emerging research field, necessitates the use of an immunocompromised xenogeneic disease model. In the present study, we addressed this issue by generating a highly immunodeficient mouse model of MPSIIIA (NOD/SCID/GammaC chain null-MPSIIIA) through five generations of crossing an established MPSIIIA mouse model and a NOD/SCID/GammaC chain null (NSG) mouse. The immune system composition, behavioural phenotype and histopathological hallmarks of the NSG-MPSIIIA model were then evaluated. We demonstrated that NSG-MPSIIIA mice display compromised adaptive immunity, ultimately facilitating the successful engraftment of human iPSC-derived neural progenitor cells in the brain up to three months post-delivery. Furthermore, female NSG-MPSIIIA exhibit spatial working memory deficits and hyperactive behaviour, similar to MPSIIIA mice, which usually manifest around 5 months of age. NSG-MPSIIIA mice also developed primary disease-related neuropathological features in common with the MPSIIIA model, including lysosomal enlargement with storage of excess sulphated heparan sulphate and increased gliosis in several areas of the brain. In the future, the NSG-MPSIIIA mouse model holds the potential to serve as a valuable platform for evaluating human stem-cell based therapies for MPSIIIA patients.

The Effectiveness of Dance Interventions on Psychological and Cognitive Health Outcomes Compared with Other Forms of Physical Activity: A Systematic Review with Meta-analysis.

BACKGROUND: Physical activity is known to improve psychological and cognitive outcomes. Learning dance sequences may challenge cognition, partnered or group dance may benefit social interactions, and the artistic aspect may improve psychological wellbeing. Dance is an equally effective form of physical activity compared with other structured physical activities to improve physical health, but it is unclear how effective dance could be for psychological and cognitive outcome measures. OBJECTIVE: To systematically review the literature on the effectiveness of structured dance interventions, compared with structured exercise programmes, on psychological and cognitive outcomes across the lifespan. METHODS: Eight databases were searched from earliest records to July 2022. Studies investigating a dance intervention lasting ≥ 4 weeks, including psychological and/or cognitive health outcomes, and having a structured exercise comparison group were included. Screening and data extraction were performed by two independent reviewers at all stages. All reviewer disagreements were resolved by the primary author. Where appropriate, meta-analysis was performed, or an effect size estimate generated. RESULTS: Of 21,737 records identified, 27 studies met the inclusion criteria. Total sample size of included studies was 1392 (944 females, 418 males, 30 unreported). Dance was equally as effective as other physical activity interventions in improving quality of life for people with Parkinson's disease [mean difference 3.09; 95% confidence interval (CI) - 2.13 to 8.30; p = 0.25], reducing anxiety (standardised mean difference 2.26; 95% CI - 2.37 to 6.90; p = 0.34), and improving depressive symptoms (standardised mean difference 0.78; 95% CI - 0.92 to 2.48; p = 0.37). Preliminary evidence found dance to be superior to other physical activity interventions to improve motivation, aspects of memory, and social cognition and to reduce distress. Preliminary evidence found dance to be inferior to other physical activity interventions to improve stress, self-efficacy and language fluency. CONCLUSION: Undertaking structured dance of any genre is generally equally and occasionally more effective than other types of structured exercise for improving a range of psychological and cognitive outcomes. TRIAL REGISTRATION: PROSPERO: CRD42018099637.

Systemic immune challenge exacerbates neurodegeneration in a model of neurological lysosomal disease.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a rare paediatric lysosomal storage disorder, caused by the progressive accumulation of heparan sulphate, resulting in neurocognitive decline and behavioural abnormalities. Anecdotal reports from paediatricians indicate a more severe neurodegeneration in MPS IIIA patients, following infection, suggesting inflammation as a potential driver of neuropathology. To test this hypothesis, we performed acute studies in which WT and MPS IIIA mice were challenged with the TLR3-dependent viral mimetic poly(I:C). The challenge with an acute high poly(I:C) dose exacerbated systemic and brain cytokine expression, especially IL-1ß in the hippocampus. This was accompanied by an increase in caspase-1 activity within the brain of MPS IIIA mice with concomitant loss of hippocampal GFAP and NeuN expression. Similar levels of cell damage, together with exacerbation of gliosis, were also observed in MPS IIIA mice following low chronic poly(I:C) dosing. While further investigation is warranted to fully understand the extent of IL-1ß involvement in MPS IIIA exacerbated neurodegeneration, our data robustly reinforces our previous findings, indicating IL-1ß as a pivotal catalyst for neuropathological processes in MPS IIIA.