Spinal manifestations of CLN1 disease start during the early postnatal period

Autor: Mark S. Sands, Jonathan D. Cooper, Joshua T. Dearborn, John R. Østergaard, Hemanth R. Nelvagal
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Physiology
Disease
GAIT ANALYSIS
Pathogenesis
ACTIVATION
Mice
0302 clinical medicine
MOUSE MODELS
CORD
BRAIN
Mice
Knockout
Neurodegeneration
neurodegeneration
batten disease
postnatal development
medicine.anatomical_structure
Neurology
SURVIVAL
Original Article
neuronal ceroid lipofuscinosis
EXPRESSION
Histology
gait
Pathology and Forensic Medicine
03 medical and health sciences
Interneurons
Neuronal Ceroid-Lipofuscinoses
Physiology (medical)
medicine
Animals
Humans
Neuroinflammation
business.industry
spinal cord
INFANTILE TYPE
Original Articles
NEURONAL CEROID-LIPOFUSCINOSIS
medicine.disease
Spinal cord
Oligodendrocyte
PATHOLOGY
030104 developmental biology
Animals
Newborn
Neuronal ceroid lipofuscinosis
Neurology (clinical)
Astrocytosis
Thiolester Hydrolases
business
030217 neurology & neurosurgery
Zdroj: Neuropathology and Applied Neurobiology
Nelvagal, H R, Dearborn, J T, Ostergaard, J R, Sands, M S & Cooper, J D 2021, ' Spinal manifestations of CLN1 disease start during the early postnatal period ', Neuropathology and Applied Neurobiology, vol. 47, no. 2, pp. 251-267 . https://doi.org/10.1111/nan.12658
ISSN: 1365-2990
0305-1846
DOI: 10.1111/nan.12658
Popis: The spinal cord appears especially vulnerable in CLN1 disease, a fatal inherited lysosomal storage disorder. Our data reveal a much earlier onset of spinal cord disease and accompanying behavioural changes in CLN1 mice, 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.
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.
Databáze: OpenAIRE
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