Why does impaired protein degradation lead to neuronal hyperexcitability and disturbed cortical functions?

Several brain disorders are associated with impaired protein degradation and, despite different genetic backgrounds, share some common neurological features such as disruption of sleep/circadian rhythm and epilepsy. Here we propose a unifying hypothesis that suggests a direct causal link between defective protein degradation and hyperexcitability. This link is due to a high concentration of intracellular chloride required to compensate for the loss of intracellular pressure due to the permanence of non-degraded protein clusters. During their lifetime, proteins undergo a metamorphosis from the cytosolic phase, where new-born proteins are dispersed in water, to different states of aggregation as they cluster in aggregates of many proteins. Importantly, protein degradation is also preceded by protein clustering. When protein degradation is inhibited by several possible genetic defects, the consequence is an accumulation of non-degraded protein clusters. A recent paper has demonstrated that when proteins cluster, they contribute less to osmotic pressure. This would lead to cell shrinkage, which is unacceptable in a complex organ, and thus, the loss of pressure is compensated by the influx of several ions including chloride. The chloride load has an important effect in neurons: it weakens synaptic inhibition, the mechanism that protects the brain from excessive excitation, and that plays an important part in cognitive functions. Our hypothesis suggests a role of intracellular chloride in these heterogeneous diseases, suggesting a common druggable target. We will verify this hypothesis in two models of pathologies characterized by defective degradation: a model for Ceroid Lipofuscinosis 1 and a model of Angelman disease.