Journal
BRAIN
Volume 136, Issue -, Pages 1083-1101Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awt020
Keywords
neuronal ceroid lipofuscinosis; neurodegeneration; neuroinflammation; T-lymphocytes; axonal damage
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Funding
- NCL-Foundation, Hamburg
- R + W foundation, Klingenberg
- German Research Foundation [SFB 581]
- University of Wuerzburg
- Batten Disease Family Association (BDFA)
- Batten Disease Support and Research Association (BDSRA)
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The neuronal ceroid lipofuscinoses are fatal neurodegenerative disorders in which the visual system is affected early in disease progression. A typical accompanying feature is neuroinflammation, the pathogenic impact of which is presently obscure. Here we investigated the role of inflammatory cells in palmitoyl protein thioesterase 1-deficient (Ppt1(-/-)) mice, a model of infantile neuronal ceroid lipofuscinosis (CLN1 disease, infantile), predominantly focusing on the visual system. We detected an early infiltration of CD8+ T-lymphocytes and observed activation of microglia/macrophage-like cells. To analyse the pathogenic impact of lymphocytes, we crossbred Ppt1(-/-) mice with mutants lacking lymphocytes (Rag1(-/-)), and scored axonal transport, axonal perturbation and neuronal survival. This lack of lymphocytes led to a significant amelioration of disease phenotypes, not only in the retino-tectal system, but also in other regions of the central nervous system. Finally, reconstitution experiments revealed a crucial role of CD8+ T-lymphocytes in pathogenesis. Our study provides novel pathomechanistic insights that may be crucial for developing treatment strategies.
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