Nelvagal, HR;
Dearborn, JT;
Ostergaard, JR;
Sands, MS;
Cooper, JD;
(2021)
Spinal manifestations of CLN1 disease start during the early postnatal period.
Neuropathology and Applied Neurobiology
, 47
(2)
pp. 251-267.
10.1111/nan.12658.
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Abstract
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 in Ppt1−/− 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 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. 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.
| Type: | Article |
|---|---|
| Title: | Spinal manifestations of CLN1 disease start during the early postnatal period |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/nan.12658 |
| Publisher version: | https://doi.org/10.1111/nan.12658 |
| Language: | English |
| Additional information: | © 2020 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
| Keywords: | batten disease, gait, neurodegeneration, neuronal ceroid lipofuscinosis, postnatal development, spinal cord, Animals, Animals, Newborn, Humans, Interneurons, Mice, Mice, Knockout, Neuronal Ceroid-Lipofuscinoses, Spinal Cord, Thiolester Hydrolases |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10144988 |
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