Sheep Chimera Study Points Up Role of Brain Inflammation in Batten

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An inflammatory environment driven by brain cells called microglia may act to prevent the brain from repairing itself in Batten disease, according to a new study done in sheep chimeras.

The study, “Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease),” was published in PLOS One.

The most well-characterized large animal model of Batten disease is a version that naturally can occur among South Hampshire sheep in New Zealand. This sheep form of the disease is associated with mutations in the gene CLN6, and its progression is comparable to a human form of late infantile Batten disease caused by mutations in the human version of the CLN6 gene.

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In a genetic disorder like Batten disease, every cell in a person’s body is affected. Consequently, it can be difficult to untangle precisely which changes are most integral to driving disease processes — and, as such, could benefit most from targeted treatment.

To learn more, scientists in New Zealand created chimeric sheep. Chimeras — named for the creature from Greek mythology with a lion’s head, goat’s udders, and snake’s tail — are organisms that are made of two or more sets of genetically distinct cells. Simplistically, here the scientists took sheep embryos with or without Batten disease, from very early in development, and mixed the cells together such that only one sheep would develop.

“The resultant 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 closely resembling sheep with Batten disease were classified as “affected-like”; these sheep were both blind and displayed markedly reduced brain volumes.

Another two sheep, with the least apparent changes, were classified as “normal-like.” The remaining three sheep, between these two extremes, were termed “recovering-like” because their brain volume was reduced early in life, but increased to nearer normal ranges as they aged. Notably, none of the “recovering-like” sheep were blind.

The researchers conducted detailed analyses of the sheep’s brains. A notable finding was that the more severely affected chimeras showed a pronounced increase in the activity of microglia in their brains, whereas “normal-like” sheep showed little microglia activation. Microglia are the brain’s resident immune cell, responsible for fighting off infectious invaders by launching inflammatory attacks — but uncontrolled inflammation can cause damage to brain tissue.

The researchers also showed that markers of neurogenesis (the generation of new nerve cells) were higher than normal in all of the chimeras, particularly the “affected-like” sheep — even though these sheep still ended up having the smallest brain volumes.

Taking these findings together, the researchers suggested that the inflammatory environment triggered by microglia in the more severely affected sheep may have made it harder for the brain — particularly the portions unaffected by Batten disease — to rebuild and recover from damage caused by the disease.

“The intracranial volume data suggest that migration of corrected cells, in combination with a neurotrophic environment, results in newly generated cell survival, leading to recovering intracranial volumes and disease amelioration,” they wrote.

A noteworthy implication of this result, the researchers said, is that there appear to be interactions between normal and Batten-affected cells in the sheep’s brains, suggesting that defects caused by the disease don’t only affect the cell carrying the mutation, but also nearby cells.

“The fact that normal cells appeared to alter the fate of affected cells in the normal-like and recovering-like chimeras suggests that the CLN6 protein may be involved in the processing of secreted factors, which when released provide a specific survival or anti-apoptotic signal to affected cells or create a better growth environment able to support CLN6-deficient cells,” the team concluded.