Protein aggregation as a possible cause for pathology in a subset of familial Unverricht-Lundborg disease.

Loss of function mutations in the gene (CSTB) encoding human cystatin B, a widely expressed cysteine protease inhibitor, are responsible for a severe neurological disorder known as an Unverricht-Lundborg disease (EPM1). EPM1 had been linked to chromosome 21q22.3 in Finnish families and it is an autosomal recessive inherited disorder with a homozygous minisatellite expansion in the cystatin B gene (stefin B gene). This disease is difficult to treat because it is refractory to most antiepileptic drugs and using multiple medications had been unsuccessful so far. To come a step closer to understanding of the nature of this disease, especially about the events on the molecular level, in vitro properties of missense EPM1 mutant G4R were determined. It was observed that the mutant has a prolonged lag phase of fibrillation at the same protein stability, which could indicate it were more toxic to the cells. Similar experiments with the N-terminal fragment of 67 aminoacid residues are ongoing, showing higher propensity to aggregate. Therefore, a hypothesis is launched that at least in a subset of Unverricht-Lundborg disease patients, cystatin B protein may aggregate in the cell. Protein aggregation can be secondary to external insults or aging, however, inherited forms of neurodegenerative diseases, such as familial Parkinson's, Huntington's or familial Alzheimer's disease, are directly linked to the mutant proteins aggregation. Protein aggregates in the form of amyloid plaques, neurofibrilary tangles, intra-cytoplasmic or intra-nuclear inclusions lead to increased production of the reactive oxygen species and dysfunction of the ubiquitine/proteasome system. Finally, mitochondrial dysfunction and cell death are observed. Certainly, it remains to be checked by experiments whether overexpression in cell culture of the missense mutants G4R and N-terminal fragment to residue 68 lead to cellular inclusions and the accompanying changes characteristic for the conformational disorders.