Spinal manifestations of CLN1 disease start during the early postnatal period.

Abstract

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. 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. We detected significant microglial activation in Ppt1-/- spinal cords at 1month. This was followed by astrocytosis, selective interneuron loss, altered spinal volumes and oligodendrocyte maturation at 2months, before significant storage material accumulation and lymphocyte infiltration at 3months. 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 2months when Ppt1-/- 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. These data reveal disease onset 2months (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.