Neuronal death mechanisms in cerebellar Purkinje cells

Heitz, Stéphane. Neuronal death mechanisms in cerebellar Purkinje cells. 2008, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_8495

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Neuropathologies often involve apoptosis and autophagy, two mechanisms of programmed cell death which require activation of specific signaling pathways. Determining the specific death pathways operating in different types of neurons in various pathological situations is important to gain insight into the strategies for preventing loss of central neurons.
My investigations were focused on cerebellar Purkinje cells in mouse models of mutations specifically affecting these neurons. Purkinje cell death was investigated in Lurcher and hotfoot mice with mutations in the Grid2 gene coding for the glutamatergic receptor GluR2, and in the Nagasaki Prnp0/0 (NP0/0) mutant mouse deficient for the prion protein and overexpressing its neurotoxic paralogue Doppel.
The mutated glutamatergic receptor GluR2Lc was shown to induce autophagy preceding excitotoxic cell death in the Purkinje cells of the heteroallelic GluR2Lc/ho mutant mouse. The present studies in organotypic cerebellar cultures elucidate a link between autophagy and excitotoxicity in the GluR2Lc/+ Purkinje cells which are rescued from excitotoxic cell death and do not display autophagy anymore after treatment with the channel blocker NASP. Excitatory synaptogenesis of Purkinje cells with parallel and climbing fibers is known to involve GluR2. Indeed, my present data indicate that somato-dendritic translocation of climbing fibers during postnatal development of Purkinje cells could be regulated by a GluR2-dependent control of Purkinje cell dendritic growth.
In the absence of prion protein in the Nagasaki mutant mouse, its paralogue Doppel induces progressive Purkinje cell loss that involves Bcl-2 family members of the intrinsic apoptotic pathway such as BAX. The partial rescue of Purkinje cells in NP0/0:Bax-/- and NP0/0-Hu-bcl-2 double mutants indicate the contribution of a BAX-independent cell death pathway. This process may occur either by autophagy which is detected early at the axonal level as evidenced by increased expression of autophagic markers and electron microscopy or by an unidentified extrinsic apoptotic mechanism.
These data suggest that different pathogenic stimuli trigger different cell death modalities involving apoptosis and autophagy in the same neuron. The interplay between these multiple pathways of programmed cell death needs to be further investigated in animal models of neurodegenerative diseases to provide new therapeutic approaches.
Advisors:Rüegg, Markus A.
Committee Members:Scheiffele, Peter and Poisbeau, Pierrick
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A. and Scheiffele, Peter
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8495
Thesis status:Complete
Number of Pages:198
Identification Number:
edoc DOI:
Last Modified:22 Apr 2018 04:30
Deposited On:13 Feb 2009 16:52

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