Autophagy in Hereditary Cystatin C Amyloid Angiopathy.
Hereditary cystatin C amyloid angiopathy is a genetic disease found only in Iceland which leads to brain hemorrhages at an early age. Patients suffering from the disease have a single mutated copy of the cystatin C gene, which renders the protein less stable and more susceptible to dimer- and oligomerization. The pathology is thought to be a result of toxic cystatin C aggregates and amyloid in the CNS arteries. The wild type variant of cystatin C is known to induce neuronal autophagy but it is not known whether the mutant protein does this as well. To examine the difference in induction of autophagy, HEK293T cells were treated with either wild type or mutant cystatin C, by transfection and treatment with conditioned medium. There was an increase in the autophagic marker LC3-II when transfected with either plasmid, with a reduced induction for the mutant variant. Treating cells with conditioned medium also induced autophagy, seen as an increase of LC3-II, but only the wild type showed significant increase. These results indicate that the cystatin C mutant might induce autophagy to a lesser extent than the wild type variant does. Other possibilities are that it is produced at lower level or is unstable. This could play a role in the development of the disease i.e. mutant cells could be less capable of inducing autophagy as a defensive response to extracellular aggregates.