Nerve Cells’ Dysfunction May Contribute to Neurodegeneration in Several Types of Batten’s, Mouse Study Reveals

Two types of nerve cells — microglia and astrocytes — are dysfunctional and may contribute to neurodegeneration associated with different types of neuronal ceroid lipofuscinoses (NCLs, aka Batten disease), according to a new mouse study.

However, the reasons behind these cells’ dysfunction are distinct in infantile NCL (CLN1 disease) and in the juvenile form of the disease (CLN3 disease), indicating these cells probably play different roles in different types of NCLs.

The study, “Compromised astrocyte function and survival negatively impact neurons in infantile neuronal ceroid lipofuscinosis,” was published in Acta Neuropathologica Communications.

NCLs comprise a group of several genetic lysosomal storage disorders and account for the most common cause of childhood dementia. There are three main types of childhood NCLs associated with genetic mutations in three different genes: infantile NCL, caused by mutations in the CLN1/PPT1 gene; late infantile NCL, caused by mutations in the CLN2/TPP1 gene; and juvenile NCL, caused by mutations in the CLN3 gene.

Regardless of their genetic cause, all types of NCLs share similar symptoms, including epileptic seizures, loss of vision, mental and motor abilities, and all lead to premature death.

Prior studies performed in a mouse model of CLN1 disease — genetically engineered animals that lack the PPT1 gene — revealed an abnormal local activation of a special subset of nerve cells, called glial cells, just before neuron destruction, suggesting that both processes could be linked. Glial cells, including astrocytes and microglia, are non-neuronal cells located in the central nervous system responsible for supporting and protecting neurons.

More recently, a study performed by the same team of researchers in an animal model of juvenile NCL (animals lacking the CLN3 gene) revealed that dysfunctional astrocytes and microglia were able to harm and even kill neurons lacking CLN3 when cultured in a lab dish together. This indicates glial cells have a direct role in NCL progression.

Now, these researchers explored if dysfunctional astrocytes and microglia also could contribute to neuronal death in CLN1 disease.

The team isolated atrocytes, microglia and neurons from mice lacking PPT1 and compared their properties to cells derived from normal wild type animals. Then, to study how these cells interact with each other, they grew them together in the same lab dish, using three different combinations: astrocytes with microglia; astrocytes or microglia with neurons; and all three cell types together.

When cultured together with astrocytes and microglia from mice lacking PPT1, the morphological features of both wild type (healthy) and PPT1-deficient neurons worsened dramatically. This negative effect, in particular neuronal death, was even more drastic when neurons without PPT1 were cultured together with microglia lacking PPT1.

Remarkably, when cultured together with healthy astrocytes and microglia, the morphological defects of neurons lacking PPT1 improved to some extent.

Altogether, these findings suggest that astrocytes and microglia lacking PPT1 are dysfunctional and may contribute directly to neuronal death associated with CLN1 disease.

“These data suggest that glial cells are more affected by PPT1 deficiency than previously anticipated, and this may directly influence neuron survival in CLN1 disease and it will be important to explore this also occurs in vivo,” the authors wrote.

“However, these defects in PPT1 deficient glia are quite distinct from those we recently reported in similar experiments in CLN3 disease, (…) in which a negative influence of functionally compromised glia upon neuronal survival is evident. Taken together, these data provide further evidence that although these disorders broadly share similar features, they may differ markedly in how individual cell types are impacted by disease,” the authors concluded.