Neuronal Cell Death and Restoration in the Basal Ganglia: Implications for Huntington's and Parkinson's diseases
Research output: Thesis › Doctoral Thesis (compilation)
Huntington's disease (HD) is a hereditary neurodegenerative disorder presenting with chorea, dementia and extensive striatal neuronal death. The mechanism through which the widely expressed mutant huntingtin mediates striatal neurotoxicity is unknown. Excitotoxicity, i.e. calcium-dependent cell death induced by activation of NMDA receptors, has been hypothesized to play an important role in HD. Our aim was to investigate whether mutant huntingtin alters the susceptibility of striatal neurons to NMDA receptor-induced death in vivo. In 1996 transgenic HD mice that express the N-terminal fragment of mutant huntingtin (R6/1 and R6/2 mice) were generated. Surprisingly, we found that R6 HD mice are totally resistant to striatal lesions caused by the NMDA receptor agonist quinolinic acid, and partially resistant to the mitochondrial toxin malonate. The resistance develops gradually with age in both R6/1 and R6/2 mice, and it occurs earlier in R6/2 (155 CAG repeats) than in R6/1 (115 CAG repeats) mice. Therefore, the resistance to excitotoxins in the striatum is dependent on both the CAG repeat length and the age of the transgenic mice. However, there is a trend towards increased susceptibility to striatal excitotoxicity in very young R6/1 mice. The development of the resistance correlates with the appearance of nuclear huntingtin inclusions in R6 mice. Interestingly, NMDA receptor-induced current and calcium influx in striatal R6 HD neurons are not altered. However, R6 HD neurons have a better capacity to handle the cytoplasmic calcium overload following NMDA receptor activation. We hypothesize that the N-terminal fragment of mutant huntingtin induces a sublethal grade of excitotoxicity. This might cause an adaptation of R6 HD neurons to excitotoxic stress. In 1999 transgenic HD mice were generated that express full-length mutant huntingtin. Interestingly, we found that these mice are more susceptible to NMDA receptor-induced striatal toxicity, indicating that excitotoxicity might play an important role in HD. Parkinson's disease (PD) is a neurodegenerative disorder characterized by rigidity, tremor, bradykinesia and depletion of striatal dopamine. Transplantation of dopaminergic neurons to the striatum can efficiently reduce symptoms in PD patients. However, the majority of implanted dopamine neurons die, at least in part through apoptosis. We found that treatment with the caspase inhibitor ac-YVAD-cmk increases the survival of dopaminergic neurons grafted to hemiparkinsonian rats, and thereby significantly improves functional recovery. When ac-YVAD-cmk is combined with the lazaroid tirilazad mesylate the two drugs had an additive effect on the survival. This indicates that both caspases and free radicals are important mediators of the death of transplanted dopaminergic neurons. In addition, we showed that the calcineurin inhibitors FK506 and cyclosporin A improve the survival of grafted dopaminergic neurons. In summary, R6 HD mice develop a resistance to striatal excitotoxicity over time, even though there is a trend for increased sensitivity at early ages. HD mice expressing full-length mutant huntingtin are more susceptible to excitotoxicity in the striatum, indicating that alterations in NMDA receptor-induced death may play a major role in HD. Furthermore, we found that inhibition of caspases, lipid peroxidation, and calcineurin increase the survival of dopaminergic neurons transplanted into the striatum.
|Research areas and keywords||
Subject classification (UKÄ) – MANDATORY
|Award date||2001 Nov 30|
|Publication status||Published - 2001|
Defence details Date: 2001-11-30 Time: 10:00 Place: Segerfalksalen, Wallenberg Neuroscience Center External reviewer(s) Name: DiFiglia, Marian Title: Professor Affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, USA. ---