PhD defence B. Honrath

On the impact of neuronal K_Cachannels & calcium signaling in neurodegeneration

Neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease are characterized by an irreversible loss of neurons in different brain areas. So far, treatment options only target symptoms but not the disease pathology.

In her thesis, Birgit Honrath exploited new protective strategies for the treatment of neurodegenerative diseases by investigating small conductance calcium-activated potassium (KCa) channels and associated calcium signaling. KCa channels prevent increases in neuronal excitability, a key factor that contributes to neuronal death.

Honrath found that pharmacological activation of KCa channels protected neuronal cells from oxidative cell death associated with mitochondrial dysfunction through regulating mitochondrial respiration and mitochondrial calcium uptake. Mitochondrial function also depends on calcium transfer between the endoplasmic reticulum (ER) and mitochondria. Using two approaches, she showed that this signaling axis has a substantial impact on neuronal survival. On the one hand, blocking this route of calcium prevented oxidative cell death. On the other hand, promoting ER-mitochondrial interactions increased mitochondrial calcium uptake, impaired mitochondrial respiration and accelerated cell death. In conditions of enhanced ER-mitochondrial connectivity, KCa channel activation still provided protection against oxidative stress induced by the neurotransmitter glutamate but not by the anti-cancer agent auranofin, indicating potential effects of KCa channels beyond neuroprotection. Furthermore, Honrath found that KCa channels are involved in the development of epilepsy, a disorder characterized by neuronal hyperactivity, and we identified a potential new regulatory mechanism of KCa channels by small non-coding microRNAs.

Thus, this thesis elaborated KCa channel activation as a strategy to preserve neuronal cell survival in different neuropathological conditions.

Dissertation

Promotores: Prof.dr. M. Schmidt