Spinal manifestations of CLN1 disease start during the early postnatal period

Aim To understand the progression of CLN1 disease and develop effective therapies we need to characterize early sites of pathology. Therefore, we performed a comprehensive evaluation of the nature and timing of early CLN1 disease pathology in the spinal cord, which appears especially vulnerable, and how this may affect behaviour. Methods We measured the spinal volume and neuronal number, and quantified glial activation, lymphocyte infiltration and oligodendrocyte maturation, as well as cytokine profile analysis during the early stages of pathology in Ppt1-deficient (Ppt1(-/-)) mouse spinal cords. We then performed quantitative gait analysis and open-field behaviour tests to investigate the behavioural correlates during this period. Results We detected significant microglial activation inPpt1(-/-)spinal cords at 1 month. This was followed by astrocytosis, selective interneuron loss, altered spinal volumes and oligodendrocyte maturation at 2 months, before significant storage material accumulation and lymphocyte infiltration at 3 months. The same time course was apparent for inflammatory cytokine expression that was altered as early as one month. There was a transient early period at 2 months whenPpt1(-/-)mice had a significantly altered gait that resembles the presentation in children with CLN1 disease. This occurred before an anticipated decline in overall locomotor performance across all ages. Conclusion These data reveal disease onset 2 months (25% of life-span) earlier than expected, while spinal maturation is still ongoing. Our multi-disciplinary data provide new insights into the spatio-temporal staging of CLN1 pathogenesis during ongoing postnatal maturation, and highlight the need to deliver therapies during the presymptomatic period.

Automated summary

This study investigated the early pathology of CLN1 disease in the spinal cord of Ppt1-deficient mice, revealing significant microglial activation at 1 month, followed by astrocytosis and other changes at 2 months, and accumulation of storage material and lymphocyte infiltration at 3 months. Inflammatory cytokine expression was altered as early as one month. Behavioral abnormalities were observed at 2 months before a decline in overall locomotor performance. Early onset of the disease 2 months earlier than expected indicates the need for therapies during the presymptomatic period.