Cleaning Up Epilepsy and Neurodegeneration: The Role of Autophagy in Epileptogenesis

摘要

Most intriguingly, the findings from this study raise the possibility that impaired autophagy could result in protein aggregates, which, in addition to being implicated in classic neurodegenerative diseases, might also play a novel role in epilepsy. While epilepsy has a variety of primary and secondary neurologic etiologies, epilepsy per se is not traditionally viewed as a neurodegenerative disorder. However, Lafora body disease, a rare progressive myoclonic epilepsy, is characterized by a pathological hallmark of cytoplasmic inclusions (Lafora bodies) owing to mutation in laforin, a protein phosphatase. Laforin has been shown to stimulate autophagy in an mTOR-dependent fashion, suggesting that impaired autophagy resulting from laforin mutations accounts for the cytoplasmic aggregates and possibly epilepsy in this disorder (9). While Lafora body disease represents a true neurodegenerative disorder, the possibility of protein aggregates contributing to primary “idiopathic” epilepsies has recently also been proposed. In particular, in a rare familial case of generalized epilepsy with febrile seizures plus (GEFS+), a mutant GABAA receptor subunit has been found to exhibit abnormally slow degradation and the formation of protein aggregates, similar to classic neurodegenerative disorders (10). Although the mechanism of this protein aggregation is not established, this mutant GABAA receptor is at least partially degraded by lysosomes, suggesting the potential involvement of impaired autophagy. Regardless of whether defective autophagy is a primary cause of the protein aggregation and epilepsy in these cases, these findings still suggest a novel therapeutic approach of using autophagy inducers, such as rapamycin, to treat epilepsy.