2026/03/05 by Alina Malyutina, Carina Lund, Saara Tegelberg +4 · 1 voice
Medicine · #Cerebrovascular and genetic disorders #Clusterin in disease pathology #Glycogen Storage Diseases and Myoclonus
paper · pdf · doi:10.1242/dmm.052681
openalex publication_date 2026/03/05 · openalex created_date 2026/03/06 · openalex updated_date 2026/08/03
Progressive myoclonus epilepsy type 1 (EPM1) is a rare neurodegenerative disease caused by partial loss of function of cystatin B (CSTB), a cysteine protease inhibitor with known neuroprotective roles. The disease mechanisms remain largely unsolved, and no treatments are available to control the debilitating myoclonus in EPM1. We investigated the impact of CSTB loss on transcriptome and proteome in three regions of CSTB-deficient (Cstb-/-) mouse brain - the cerebellum, cerebral cortex and hippocampus - during disease progression, providing comprehensive insights into the molecular changes and disease mechanisms. We elucidated three critical pathways as potential therapeutic targets. First, significant upregulation of immune response genes indicates heightened immune activity across all brain regions. Second, consistent downregulation of the oxidative phosphorylation pathway with differential expression of mitochondrial genes implies impaired energy metabolism primarily affecting the cerebellum. Third, upregulation of genes essential for lysosomal function with simultaneous downregulation of genes encoding proteins crucial for lysosomal acidification suggests lysosomal dysfunction as an essential pathogenetic mechanism. By combining proteome with transcriptome data, we identified clusterin, apolipoprotein E, peroxiredoxin 6, cathepsin D and aldolase C as potential biomarkers for disease progression.