This thesis investigates the possible role of apoptosis, or programmed cell death, in Huntington's disease (HD). HD is caused by an expanded CAG repeat in the N-terminal region of the huntingtin protein leading to specific neostriatal neurodegeneration. The sequence of events that leads to this selective neuronal death is unknown, but inappropriate activation of apoptosis may be involved. To study mechanisms of apoptotic cell death in HD, we developed animal models using the mitochondrial toxin 3-nitropropionic acid (3-NP) that induces specific neuronal death in the striatum and resembles the characteristic HD neuropathology in a wide spectrum. Apoptotic features at various time points of the process were studied in the 3-NP in vivo model, in 3-NP-exposed organotypic slice cultures and in brains of HD patients. We found an increased expression of several regulatory proteins (such as Bax, Bcl-2, caspase-3 and PARP) that are involved in the apoptotic cascade combined with typical TUNEL labeling. These findings do provide evidence for activation of apoptosis in both the 3-NP models of HD and in human HD. In addition, we examined neuroprotective effects of the bioenergetic compound creatine in the 3-NP in vitro model. Our findings suggest that creatine can prevent 3-NP-induced neurodegeneration in the cortex, while in striatal cells it may lead to accelerated and increased execution of apoptotic cell death in order to prevent further necrosis-related damage in this region. Although, the in vivo and in vitro 3-NP models used in this thesis represent one aspect of human HD, they are suited to perform different types of studies. The 3-NP slice culture system may be useful for screening new therapeutic agents, whereas the 3-NP in vivo model may be used neuropathologically for further elucidating apoptotic processes and pathways that are involved in the selective striatal neurodegeneration.

Promotor : Kremer, H.P.H. Co-promotores : Donkelaar, H.J. ten, Verbeek, M.M.

Contains fulltext : 27012.pdf (Publisher’s version ) (Open Access)

RU Radboud Universiteit Nijmegen, 02 november 2005

127 p.