Organelle specific mechanisms of neuronal cell death

Neuronal cell death caused by excitotoxicity accompanies neurodegenerative disorders, such as Alzheimer s disease (AD) and Huntington s disease (HD), epilepsy and ischaemia. Glutamate is the major excitotoxin in the CNS and causes activation of glutamate receptors. Ionotropic glutamate receptors can directly cause calcium influx that further enables activation of cell death pathways. Kainic acid (KA) is a specific agonist for ionotropic non-NMDA glutamate receptors, namely KA and AMPA receptors. KA induces epiletic activity in rodents and causes hippocampal sclerosis, similar to human temporal epilepsy. HD, a neurodegenerative disease characterized by accumulation of mutant huntingtin protein, and causing cell death in the striatum of affected individuals, has also been shown to involve excitotoxic cell death. Intracellular organelles have been implicated in stress sensing and contribute to cell death signaling. Mitochondria have been closely linked to apoptotic pathways and recent research has also implicated other organelles, such as the endoplasmic reticulum (ER), lysosomes and Golgi apparatus in cell death. In this thesis, the involvement of ER stress was shown to accompany hippocampal cell death caused by KA in vivo and in vitro as well as in a cell model of HD. KA induced activation of ER stress sensors that aim to restore homeostasis via activation of the unfolded protein response (UPR). In prolonged stressful conditions, the UPR activates apoptotic pathways. Treatment with an ER stress inhibitor, Salubrinal (Sal), significantly attenuated cell death in hippocampal neurons in vivo and in vitro. ER stress was also activated in a cell model of HD and treatment with Sal reduced cell death and mutant hungtingtin aggregation. These data indicated for the first time the involvement of the ER in cell death pathways caused by excitotoxicity, and that inhibition of ER stress could be a potential treatment against neuronal cell death in HD and other disorders involving excitotoxicity. In search of other cell death mediators we focused on Cdk5 that has been implicated deregulated in excitotoxicity. Involved in multiple signaling pathways, Cdk5, has been implicated, for instance, in regulation of synaptic proteins, ER stress and cell death. In this thesis, a KA receptor important for mediating cell death in the hippocampus, GluR6, was shown to be regulated by Cdk5. Inhibition of Cdk5 reduced GluR6 downregulation by KA as well as cell death caused by KA in vitro. These data indicated Cdk5 involvement in KA excitotoxicity and could also present a potential drug target in neurological disorders. Moreover, this was the first time that Cdk5 was shown to contribute to KA receptor regulation.

Grantor dc:publisher

Helsingin yliopisto

Year dc:date.issued

2012

Author dc:creator

• Putkonen, Noora

• biokemia

Statement dc:rights

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Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10138/37065

OAI record oai:identifier

https://helda.helsinki.fi/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Ahelda.helsinki.fi%3A10138%2F37065