Functional role of HSP70 expression regulation in the pathogenesis of epilepsy and associated inflammatory processes
Final Report Abstract
Excessive inflammatory signaling has been confirmed as one key mechanism contributing to epilepsy development (=epileptogenesis) and to hyperexcitability in the epileptic brain. The heat-shock protein superfamily HSP70 comprises a stress-inducible HSP70i, which acts as modulator of inflammatory responses and as a ligand of Toll-like receptor 4. Our project addressed three hypotheses focusing on epilepsy- and epileptogenesis-associated expression regulation of HSP70i as well as the impact of HSP70i on seizure susceptibility and development of a hyperexcitable network. Our findings from a chronic epilepsy model in rats (electrical post-status epilepticus model) revealed a pronounced induction of neuronal HSP70i expression in the early post-insult phase, and a moderate up-regulation during the latency phase. Additional analysis of further members of the HSP70 superfamily provided information about the differential expression patterns of HSPA5 and HSPH4, two cell stress-triggered proteins which serve a chaperone function targeting misfolded peptides during prolonged stress conditions. While data from the chronic phase of the rat epilepsy model pointed to a regionally restricted overexpression of both proteins, a more complex regulation pattern became evident in the early post-status epilepticus phase. In the canine brain from patients with idiopathic epilepsy, HSP70i expression was increased in the piriform lobe. Interestingly, we also confirmed an overexpression of HSPH4, of TLR4 and of High-mobility group box protein 1 (HMGB1; another ligand of TLR4) in hippocampal subregions of the canine epileptic brain. An assessment in a genetic mouse model of Dravet syndrome did not confirm a relevant regulation of HSPA5 in different brain regions of interest in this model of a developmental and epileptic encephalopathy. Analysis in this paradigm has been focused on the HSP70 superfamily member considering proteomic data sets that we obtained by comparison of hippocampal tissue from Dravet and wildtype mice. HSP70i overexpression in mice resulted in functionally relevant effects on seizure development and progression in the amygdala kindling model. The findings suggested pro-convulsant effects of elevated HSP70i levels promoting ictogenesis in naïve animals, and provided first evidence that HSP70i may also contribute to epileptogenesis. Surprisingly, findings from HSP70i knockout mice pointed to a protective role of HSP70i with an impact on spread of seizure activity. Administration of the positive HSP70i modulator Celastrol resulted in detrimental effects with reduced post-kindling thresholds and enhanced microglia activation. Taken together these findings suggest that normal expression rates of HSP70i can exert relevant protective effects and control neuronal excitability. However, an increased expression of HSP70i triggered by acute neuronal cell stress can have detrimental consequences. Thus, targeting strategies should aim to prevent a stress-induced up-regulation of HSP70i but avoid an interference with basal expression and function of HSP70i.
Publications
- 2017. A systems level analysis of epileptogenesis-associated proteome alterations. Neurobiol Dis. 105:164-178
Keck M, Androsova G, Gualtieri F, Walker A, von Rüden EL, Russmann V, Deeg CA, Hauck SM, Krause R, Potschka H
(See online at https://doi.org/10.1016/j.nbd.2017.05.017) - 2017. Identification of brain regions predicting epileptogenesis by serial [18F]GE-180 positron emission tomography imaging of neuroinflammation in a rat model of temporal lobe epilepsy. Neuroimage Clin. 15:35-44
Russmann V, Brendel M, Mille E, Helm-Vicidomini A, Beck R, Günther L, Lindner S, Rominger A, Keck M, Salvamoser J, Albert NL, Bartenstein P, Potschka H
(See online at https://doi.org/10.1016/j.nicl.2017.04.003) - 2017. Neuroinflammation imaging markers for epileptogenesis. Epilepsia. 58(Suppl.3):11-19
Koepp M, Arstad E, Bankstahl J, Dedeurwaerdere S, Friedman A, Potschka H, Ravizza T, Theodore W, Baram T
(See online at https://doi.org/10.1111/epi.13778) - 2018. Genetic modulation of HSPA1A accelerates kindling progression and exerts pro-convulsant effects. Neuroscience. 386:108-120
von Rüden EL, Wolf F, Keck M, Gualtieri F, Nowakowska M, Oglesbee M, Potschka H
(See online at https://doi.org/10.1016/j.neuroscience.2018.06.031) - 2018. Proteomic profiling of epileptogenesis in a rat model: Focus on cell stress, extracellular matrix and angiogenesis. Neurobiol Dis.112:119-135
Keck M, van Dijk, RM, Deeg CA, Kistler K, Walker A, von Rüden EL, Russmann V, Hauck SM, Potschka H
(See online at https://doi.org/10.1016/j.nbd.2018.01.013) - 2019. Epileptogenesis-associated alterations of Heat Shock Protein 70 in a rat post-status epilepticus model. Neuroscience. 415:44-58
Gualtieri F, Nowakowska M, von Rüden EL, Seiffert I, Potschka H
(See online at https://doi.org/10.1016/j.neuroscience.2019.06.031) - 2019. Genetic and Pharmacological Targeting of Heat Shock Protein 70 in the Mouse Amygdala Kindling model. ACS Chem Neurosci. 10(3):1434-1444
von Rüden EL, Wolf F, Gualtieri F, Keck M, Hunt CR, Pandita TK, Potschka H
(See online at https://doi.org/10.1021/acschemneuro.8b00475) - 2020. Molecular alterations of the TLR4-signaling cascade in canine epilepsy. BMC Vet Res. 16(1):18
von Rüden EL, Gualtieri EL, Schönhoff K, Reiber M, Wolf F, Baumgärtner W, Hansmann F, Tipold A, Potschka H
(See online at https://doi.org/10.1186/s12917-020-2241-x) - 2020. Profiling the expression of endoplasmic reticulum stress associated with heat shock protein in animal epilepsy models. Neuroscience. 429:156-172
Nowakowska M, Gualtieri F, von Rüden EL, Hansmann F, Baumgärtner W, Tipold A, Potschka H
(See online at https://doi.org/10.1016/j.neuroscience.2019.12.015) - 2020. Regulation of Alzheimer’s disease-associated proteins during the course of epileptogenesis: differential proteomic analysis in a rat model. Neuroscience. 424:102-120
von Rüden EL, Zellinger C, Gedon J, Walker A, Bierling V, Deeg CA, Hauck SM, Potschka H
(See online at https://doi.org/10.1016/j.neuroscience.2019.08.037)
