Commentary Role of Cystatin C in Neuroprotection and Its Therapeutic Implications

Earlier studies have suggested that cystatin C (CysC) is a target for intervention in neurological disorders because its expression increases in response to brain insults, in human neurological disorders, and in animal models of neurodegenerative states. However, these studies did not clarify whether CysC up-regulation is a pathogenic factor in neurodegenerative disorders or whether it represents a neuroprotective compensatory response of the organisms aimed to prevent progression of the disease. Recent reports have shown that CysC protects neuronal cells from toxic insults induced by a variety of stimuli in vitro, 1 suggesting that therapeutic approaches aimed to either increase the levels of CysC or to mimic its action could be beneficial in neurological disorders. However, the in vivo relevance of these findings remained unclear. In this issue of the journal, the article by Kaur et al 2 presents for the first time results supporting the in vivo efficacy of CysC as a neuroprotective protein. Unverricht-Lundborg disease (progressive myoclonic epilepsy type 1 [EPM1]), caused by autosomal recessive loss-of-function mutations in the gene encoding cystatin B (CysB, also known as Stefin B), 3 is the most common cause of progressive myoclonus epilepsy worldwide. 3–5 EPM1 is relatively frequent in the western Mediterranean region but is most prevalent around the Baltic Sea. It is a neurodegenerative disorder with age of onset from 6 to 16 years, characterized by stimulus-sensitive myoclonus and tonic-clonic epileptic seizures. Ataxia, loss of coordination, and tremor develop several years after the onset of the disease. Individuals with EPM1 are mentally alert but show depression and mild decline in intellectual performance over time. 6 Cerebellar atrophy and motor cortex degeneration are largely responsible for the loss in equilibrium, correlating with the motor symptoms of the disease. 7 The diagnosis of EPM1 is confirmed by identi