Immune cells perturb axons and impair neuronal survival in a mouse model of infantile neuronal ceroid lipofuscinosis.

Abstract

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.

• Authors: Janos Groh, Thomas G Kühl, Chi Wang Ip, Hemanth R Nelvagal, Sarmi Sri, Steven Duckett, Myriam Mirza, Thomas Langmann, Jonathan D Cooper, Rudolf Martini
• Journal: Brain : a journal of neurology (Brain) Vol. 136 Issue Pt 4 Pg. 1083-101 (Apr 2013) ISSN: 1460-2156 [Electronic] England
• PMID: 23485853 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Thiolester Hydrolases
• palmitoyl-protein thioesterase

Topics

• Animals
• Axons (immunology, pathology)
• Disease Models, Animal
• Inflammation (genetics, immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neuronal Ceroid-Lipofuscinoses (genetics, immunology, pathology)
• Neurons (immunology, pathology)
• Phenotype
• T-Lymphocytes
• Thiolester Hydrolases (deficiency, genetics)