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An examination of the spinal cord of mice lacking the PPT1 protein, the underlying cause of infantile Batten disease, revealed loss of specific neurons, signs of inflammation, and gait abnormalities that began early in spinal cord development, study reports.

These findings support the identification and treatment of children with infantile Batten disease before symptoms appear.

The study, “Spinal manifestations of CLN1 disease begin early in the postnatal period, ”Was published in the journal Neuropathology and Applied Neurobiology.

Infantile Batten disease, or CLN1 disease, is caused by mutations in the PPT1 gene, which provides instructions for making the protein PPT1, which normally removes fat – called long-chain fatty acids – from certain proteins, which helps break down proteins.

Mutations cause loss of the PPT1 protein, leading to the buildup of fatty waste deposits called lipofuscins in cells of the eye, brain, spinal cord, as well as muscle, skin, and many other tissues. , resulting in cell death at a very young age.

Symptoms appear between the ages of 2 and 24 months and are characterized by a lack of weight gain, seizures and loss of motor skills. Currently, there are no effective therapies for childhood Batten disease other than symptom management.

Studies have identified significant spinal cord damage (pathology) in CLN1 children, but how these changes occur in the early stages of the disease is poorly understood. As such, an analysis of the cellular and molecular changes resulting from PPT1 deficiency in its initial stages is essential to design effective therapies.

To do this, researchers based at Washington University at St. Louis conducted a detailed analysis of the spinal cord of mice deficient in the PPT1 gene in the early stages of life. The results were compared tWashington University at St. Louis o the spinal cord of healthy mice.

These mutant mice mimic most human symptoms, including shortened lifespan (typically 7.5-8 months in mice), visual defects, seizures, and walking (gait) problems later in the progression of disease.

They also show a pronounced build-up of auto-fluorescent storage material (AFSM), a component of lipofuscin, and the activation of brain immune cells called microglia, which results in loss of nerve cells (neurons) in the brain and the brain. retina in the eye.

A study of the spinal cord at the age of two months found a significant reduction in spinal interneurons, nerve cells that relay signals between sensory neurons and motor neurons. There was no sign of loss in other types of spinal neurons.

Early alterations in the production of nerve cell signaling molecules known as neuropeptides were shown to parallel the onset of loss of interneurons. Accumulation of AFSM, a hallmark of CLN1 disease, did not occur in the spinal cord of mutant mice for three months.

An examination of immune cells, including microglia, revealed that they were activated in the spinal cord at the onset of the disease, as early as one month old, at least two months earlier than previously reported. In addition, there was a dramatic increase in white blood cells known as CD4 and CD8 positive lymphocytes at three months.

Accompanying the changes in immune cells, immune signaling proteins, called cytokines, increased from 1 month onwards compared to healthy mice, which corresponded to “the onset of microglial activation at that time.”

During the growth of healthy mice, the volume of the spinal cord increases from birth to three months. While the spinal cord volume of mutant mice was the same as that of healthy mice at one month, the volume of mutant mice was significantly less than that of healthy mice from 2 months.

Other experiments revealed impaired development of neurons called oligodendrocytes, which support and isolate nerve fibers, explaining the loss of volume in the spinal cord.

A 1 month walk test revealed no difference between mutant mice and healthy mice. However, at 2 months, the mutant mice outperformed healthy mice, earlier and by taking larger steps, which normalized at 3 months. Beyond that, the mutant mice gradually declined for all walking parameters.

To determine if the early changes in gait were sustained over longer periods of time, the team assessed one-hour movement activity focusing on mice at 1, 2, and 3 months. Mutant mice walked significantly shorter distance, fewer steps, and more rests per hour than healthy mice at all stages of development.

A video analysis of the walking skills of an infantile patient with Batten disease revealed early motor abnormalities at 2 years and 4 months of age, which showed non-rhythmic gait, with periods of pause followed by walking faster than usual in an uncoordinated fashion. . This observation was consistent with that of the mutant mice in this study.

“Our data places the onset of selective neuron loss, neuroinflammatory cascade, and gait abnormalities that all begin during the period when the spinal cord is still developing,” the researchers wrote. “Our data suggest that postnatal maturation appears to be impaired and that there may be an interaction between neurodegeneration and developmental processes that has so far been underestimated.”

“These data highlight the need to initiate treatment as soon as possible, and although this is feasible in a mouse model, it has important implications for identifying and treating CLN1 children while they are presymptomatic,” he said. they added.

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