The autosomal recessively inherited progressive myoclonus epilepsy of Unverricht- Lundborg type (EPM1, OMIM 254800) is a neurodegenerative disease severely affecting patients motor coordination. Its onset lies around 6 to 16 years of age and the presenting symptoms are severely incapacitating, stimulus-sensitive myoclonus and/or tonic-clonic seizures. Later during disease course, the patients develop ataxia. EPM1 is caused by mutations in the cystatin B (CSTB, OMIM 601145) gene, encoding the cysteine protease inhibitor CSTB. The CSTB-deficient mouse (Cstb-/- mice) is characterized by neuronal hyperexcitability and brain atrophy. In addition, histological studies revealed that the neuronal pathology is accompanied by early microglial activation. Aberrant activation of microglia and neuroinflammation has previously been linked to neuropathology and neurodegenerative diseases. Therefore, we aimed to characterize microglia of Cstb-/- mice in more detail. Our results identified impaired interferon signaling as a potential molecular pathway underlying the phenotype of Cstb-/- mice. In addition, functional properties of activated primary Cstb-/- microglia are altered in vitro. For example, their chemokine release is enhanced, but their phagocytic activity is reduced. In pre-symptomatic Cstb-/- mouse brains at postnatal day 14, the activation of Cstb-/- microglia is shifted towards an anti-inflammatory activation, and it switches towards a pro-inflammatory activation in early symptomatic Cstb-/- mice at postnatal day 30. In line with this, inflammatory markers are upregulated, and T lymphocytes and granulocytes exist in the brain of Cstb-/- mice, which suggests an infiltration of peripheral immune cells. Pro-inflammatory activated macrophages in the spleen imply a widespread immune system activation in Cstb-/- mice. In conclusion, we show that microglia in Cstb-/- mice are dysfunctional and that their activation is aberrant. We link CSTB deficiency in young mice to inflammatory processes and suggest that microglial dysfunction might contribute to the pathology of EPM1.
|Place of Publication||Helsinki|
|Publication status||Published - 2017|
|MoE publication type||G5 Doctoral dissertation (article)|
Fields of Science
- 3112 Neurosciences