According to a new study in chimera sheep, an inflammatory environment driven by brain cells called microglia may prevent the brain from repairing itself in Batten disease.
The study, “Aggregation chimeras provide evidence for in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease)was published in PLOS One.
The best-characterized large animal model of Batten disease is a version that can occur naturally in South Hampshire sheep in New Zealand. This ovine form of the disease is associated with mutations in the gene CLN6and its progression is comparable to a human form of late childhood Batten disease caused by mutations in the human version of the CLN6 embarrassed.
In a genetic disease like Batten disease, every cell in a person’s body is affected. Consequently, it can be difficult to disentangle precisely which changes are most integral to disease processes and, as such, which would benefit most from targeted treatment.
To find out more, New Zealand scientists created chimeric sheep. Chimeras – named after the creature from Greek mythology with a lion’s head, goat’s udders and snake’s tail – are organisms made up of two or more sets of genetically distinct cells. Simplistically, here scientists took embryos from sheep with or without Batten disease, early in development, and mixed the cells together so that a single sheep developed.
“The resulting chimeras possessed varying proportions of normal and affected cells and clinical and neuropathological profiles somewhere between those of affected and normal animals,” the researchers wrote.
A total of seven chimeric sheep were created and studied. The two with symptoms and brain changes most resembling sheep with Batten disease were classified as “affected”; these sheep were both blind and displayed markedly reduced brain volumes.
Two other sheep, with the least apparent changes, were classified as ‘normal type’. The remaining three sheep, between these two extremes, were termed “recovery-like” because their brain volume was reduced early in life but increased to approach normal as they aged. Notably, none of the “recovery-like” sheep were blind.
The researchers performed detailed analyzes of the brains of the sheep. A notable finding was that the most severely affected chimeras showed a pronounced increase in microglia activity in their brains, while the “normal-type” sheep showed little microglia activation. Microglia are the brain’s resident immune cell, responsible for fighting off infectious invaders by launching inflammatory attacks – but unchecked inflammation can damage brain tissue.
The researchers also showed that markers of neurogenesis (the generation of new nerve cells) were higher than normal in all chimeras, especially the “affected” sheep, even though these sheep always ended up having the smallest volumes. cerebral.
Bringing these results together, the researchers suggested that the inflammatory environment triggered by microglia in the most severely affected sheep could have made it more difficult for the brain to rebuild – especially parts not affected by Batten disease – and recover. damage caused by disease.
“Intracranial volume data suggest that migration of corrected cells, in combination with a neurotrophic environment, results in survival of newly generated cells, leading to recovery of intracranial volumes and improvement in disease,” they wrote. writing.
A notable implication of this finding, the researchers say, is that there appear to be interactions between normal and Batten-affected cells in sheep brains, suggesting that the defects caused by the disease do not just affect the cell carrying the mutation, but also neighboring cells.
“The fact that normal cells appear to alter the fate of affected cells in normal-type and recovery-type chimeras suggests that the CLN6 protein may be involved in the processing of secreted factors, which when released provide survival specific or anti-apoptotic signal to affected cells or create a better growth environment capable of supporting CLN6-deficient cells,” the team concluded.