Author(s): Tarja Joensuu 1,2,3,*, Saara Tegelberg 1,2,3, Eva Reinmaa 1, Mikael Segerstråle 3,4,5, Paula Hakala 1,2,3, Heidi Pehkonen 6, Esa R. Korpi 6, Jaana Tyynelä 7, Tomi Taira 3,5, Iiris Hovatta 4,8, Outi Kopra 1,2,3, Anna-Elina Lehesjoki 1,2,3
Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1, OMIM 254800) is an autosomal recessively inherited neurodegenerative disease characterized by stimulus-sensitive myoclonus, tonic-clonic seizures and ataxia with the disease onset at 6-16 years of age . While epileptic seizures are usually well controlled with medication, myoclonus is resistant to treatment and severely incapacitating. EPM1 is caused by loss-of-function mutations in the cystatin B gene (CSTB ), the most common of which is an expansion of a dodecamer repeat in the promoter region of the gene , . A mouse model for the disease, the Cstb -deficient (Cstb-/- ) mouse, presents with many of the clinical features of EPM1, especially myoclonus starting at the age of 1 month and progressive ataxia manifesting around 6 months of age . One of the major neuropathological phenotypes in Cstb-/- mice is a severe loss of cerebellar granule neurons due to apoptotic death. Cerebella of Cstb-/- mice also show oxidative damage, reflected by depletion of antioxidants and increased lipid peroxidation . Moreover, we recently reported striking, early microglial activation in Cstb-/- brain, which precedes the emergence of myoclonus and is followed by widespread astroglial activation and selective neuronal loss .
CSTB is a cysteine protease inhibitor that controls the activity of lysosomal cysteine cathepsins. Cathepsin activity has been found to be increased in EPM1 patient lymphoblastoid cells . In Cstb-/- mice, cathepsin B has been shown to mediate the increased sensitivity to oxidative stress -induced cell death  and cathepsin removal or inhibition by other means to ameliorate the neurodegenerative phenotype of Cstb-/- mice , . Yet, the molecular mechanisms leading to EPM1 are still largely unknown and it is possible that CSTB has functions independent of cathepsins.
The changes in gene expression patterns may reveal dysregulated pathways and functional cascades causative for pathological processes. A previous array-based approach to study differentially expressed genes in aged, fully symptomatic 8-month-old Cstb-/- mice revealed changes in genes related to glial activation and immunological pathways, reflecting the advanced pathological state of Cstb -/- brain at that age . However, we recently reported pathological changes in Cstb-/- mice that begin with intense microglial activation already at 2 weeks of age, prior to the appearance of the first clinical symptom, myoclonus . To further understand the molecular processes involved in EPM1, we used cerebellum as a model system and generated microarray-based gene expression patterns from immature pre-symptomatic and young symptomatic cerebella and cultured cerebellar granule cells of Cstb-/- mice. Gene Ontology (GO) analysis of expression changes in presymptomatic mice highlighted disruption in synaptogenesis and in synaptic function and maintenance, and in symptomatic mice, in immune and defense response genes. Consequences in synaptic function were characterized using electrophysiological and ligand-binding analyses along with immunohistological studies in neurons...
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