Activation of Non‐neuronal Cells within the Prenatal Developing Brain of Sheep with Neuronal Ceroid Lipofuscinosis

Abstract

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are fatal inherited lysosomal storage diseases of children characterized by increasing blindness, seizures and profound neurodegeneration but the mechanisms leading to these pathological changes remain unclear. Sheep with a CLN6 form that have a human-like brain and disease progression are invaluable for studying pathogenesis. A study of preclinical pathology in these sheep revealed localized glial activation at only 12 days of age, particularly in cortical regions that subsequently degenerate. This has been extended by examining fetal tissue from 60 days of gestation onwards. A striking feature was the presence of reactive astrocytes and the hypertrophy and proliferation of perivascular cells noted within the developing white matter of the cerebral cortex 40 days before birth. Astrocytic activation was evident within the cortical gray matter 20 days before birth, and was confined to the superficial laminae 12 days after birth. Clusters of activated microglia were detected in upper neocortical gray matter laminae shortly after birth. Neuronal development in affected sheep was undisturbed at these early ages. This prenatal activation of non-neuronal cells within the affected brain indicates the onset of pathogenesis during brain development and that an ordered sequence of glial activation precedes neurodegeneration.

Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis

“…The distribution of microglial activation within the thalamus in Ppt1 −/− mice was very similar to that of astrocytosis, but accompanied significant neuronal loss, becoming more pronounced in the later stages of disease progression. However, a first wave of localized microglial activation also occurs before birth in CLN6 deficient sheep (Kay et al, 2006), before declining in the early postnatal period (Oswald et al, 2005). The significance of such early microglial responses in NCL pathogenesis remains unclear, but the distribution of this early microglial activation accurately predicts where neuronal loss subsequently occurs (Oswald et al, 2005).…”

Current therapies for the soluble lysosomal forms of neuronal ceroid lipofuscinosis

“…Early presentation of fetal inflammation in a large animal model of NCL further advocates prenatal intervention [22]. Prenatal gene therapy offers several potential advantages for the CNS: long-term expression of the gene product in post-mitotic cells, alongside the potential for transduction of stem or progenitor cells; induction of immune tolerance to the expressed protein; and finally the potential to treat the disease at the earliest possible timepoint before any irreversible damage may have occurred [23].…”

Potential for Early-Life Immune Insult Including Developmental Immunotoxicity in Autism and Autism Spectrum Disorders: Focus on Critical Windows of Immune Vulnerability

“…Suppression of microglia cell activation in early life might be neuroprotective against excitotoxic brain damage in animal models (Dommergues et al, 2003). In animal models of neurodegeneration, prenatal activation of microglia cells precedes both astrocyte activation and subsequent brain damage (Kay et al, 2006).…”