Compromised astrocyte function and survival negatively impact neurons in infantile neuronal ceroid lipofuscinosis

• Published in: Acta neuropathologica communications Vol. 6; no. 1; p. 74
• Main Authors: Lange, Jenny, Haslett, Luke J, Lloyd-Evans, Emyr, Pocock, Jennifer M, Sands, Mark S, Williams, Brenda P, Cooper, Jonathan D
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 08-08-2018; BioMed Central; BMC
• Subjects: Animals; Animals, Newborn; Apoptosis; Astrocyte and microglial dysfunction; Astrocytes - drug effects; Astrocytes - pathology; Bone marrow; Calcium - metabolism; Cell Survival - drug effects; Cells, Cultured; Cerebral Cortex - cytology; Coculture Techniques; Comparative analysis; Cytokines - metabolism; Dementia; Disease; Disease Models, Animal; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Enzymes; Genotype & phenotype; Glial Fibrillary Acidic Protein - metabolism; Infantile batten disease, CLN1 disease, neuronal ceroid lipofuscinosis; Lipopolysaccharides - pharmacology; Medical research; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins - metabolism; Morphology; Mutation; Neurodegeneration; Neuron-glial interactions; Neuronal Ceroid-Lipofuscinoses - genetics; Neuronal Ceroid-Lipofuscinoses - pathology; Neurons; Neurons - drug effects; Neurons - pathology; Proteins; Rodents; Thiolester Hydrolases - deficiency; Thiolester Hydrolases - genetics; Time Factors; Astrocyte and microglial dysfunction; Neuron-glial interactions; Infantile batten disease, CLN1 disease, neuronal ceroid lipofuscinosis
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-018-0575-4

The neuronal ceroid lipofuscinoses (NCLs) are the most common cause of childhood dementia and are invariably fatal. Early localized glial activation occurs in these disorders, and accurately predicts where neuronal loss is most pronounced. Recent evidence suggests that glial dysfunction may contribute to neuron loss, and we have now explored this possibility in infantile NCL (INCL, CLN1 disease). We grew primary cultures of astrocytes, microglia, and neurons derived from Ppt1 deficient mice (Ppt1
) and assessed their properties compared to wildtype (WT) cultures, before co-culturing them in different combinations (astrocytes with microglia, astrocytes or microglia with neurons, all three cell types together). These studies revealed that both Ppt1
astrocytes and microglia exhibit a more activated phenotype under basal unstimulated conditions, as well as alterations to their protein expression profile following pharmacological stimulation. Ppt1
astrocytes also displayed abnormal calcium signalling and an elevated cytoplasmic Ca
level, and a profound defect in their survival. Ppt1
neurons displayed decreased neurite outgrowth, altered complexity, a reduction in cell body size, and impaired neuron survival with prolonged time in culture. In co-cultures, the presence of both astrocytes and microglia from Ppt1
mice further impaired the morphology of both wild type and Ppt1
neurons. This negative influence was more pronounced for Ppt1
microglia, which appeared to trigger increased Ppt1
neuronal death. In contrast, wild type glial cells, especially astrocytes, ameliorated some of the morphological defects observed in Ppt1
neurons. These findings suggest that both Ppt1
microglia and astrocytes are dysfunctional and may contribute to the neurodegeneration observed in CLN1 disease. However, the dysfunctional phenotypes of Ppt1
glia are different from those present in CLN3 disease, suggesting that the pathogenic role of glia may differ between NCLs.