Abstract
The heat shock protein 70 (Hsp70) is upregulated in response to stress and has been implicated as a stress marker in temporal lobe epilepsy (TLE). However, whether Hsp70 plays a pathologic or protective role in TLE remains unclear. Here we report a deleterious role of Hsp70 in kainic acid (KA)-induced seizures. Hsp70 expression is upregulated in a KA model of TLE, and silencing or inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates acute or chronic epilepsy by enhancing A-type potassium current in hippocampal neurons. Hsp70 upregulation leads to proteosomal degradation of Kv4-KChIP4a channel complexes primarily encoding neuronal A-type current. Furthermore, Hsp70 directly binds to the N terminus of auxiliary KChIP4a and targets Kv4-KChIP4a complexes to proteasome. Taken together, our findings reveal a role of Hsp70 in the pathogenesisof epilepsy through degradation of Kv4-KChIP4a complexes, and pharmacological inhibition of Hsp70 may represent therapeutic potential for epilepsy or hyperexcitability-related neurological disorders.
Highlights
Epilepsy is a common neurological disorder characterized by spontaneous recurrent seizure activity that afflicts more than 65 million people worldwide (Mosheet al., 2015)
Western blot analysis showed that heat shock protein 70 (Hsp70) protein expression was significantly increased at 12, 24, and 48 hr after kainic acid (KA) injection and returned to normal at 72 hr (Figure 1B), which was coincident with induction of Status epilepticus (SE) in the rat KA model (Figure S1A)
We examined the interaction of Hsp70 with different Kv channel-interacting proteins (KChIPs) members that contain a variable N terminus and conserved C-terminal core domain. coIP analysis revealed that Hsp70 interacted only with KChIP4a, not KChIP1 or KChIP3 (Figure 5C)
Summary
Epilepsy is a common neurological disorder characterized by spontaneous recurrent seizure activity that afflicts more than 65 million people worldwide (Mosheet al., 2015). Heat shock proteins (HSPs) are ubiquitous molecular chaperones important for a variety of biological processes ranging from cellular stress response to trafficking and quality control of membrane receptors (Hartl et al, 2011). Hsp expression is upregulated during status epilepticus (Yang et al, 2008), and activating Hsp stabilizes tau proteins both in cells and brain tissues (Jinwal et al, 2009). Upregulation of Hsp exacerbates the chronic inflammation and promotes myelin autoantigen recognition (Asea et al, 2000, 2002; Mycko et al, 2008). All these observations suggest that the role of endogenous Hsp in the pathogenesis of neurological diseases remains to be understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
