TARGETING PCD IN PD · Targeting programmed cell death in Parkinson's disease

Final Activity Report Summary - TARGETING PCD IN PD (Targeting programmed cell death in Parkinson's disease)

Parkinson's disease (PD) is a common neurodegenerative disorder characterised mainly by resting tremor, slowness of movement, rigidity, and postural instability, all attributed to a dramatic loss of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNpc). Thus far, the most potent treatment for PD remains the administration of a precursor of DA, L-DOPA, which, by replenishing the brain with DA, alleviates almost all PD symptoms. However, the chronic administration of L-DOPA causes motor and psychiatric side effects, which may be as debilitating as PD itself, and does not impede the progressive death of SNpc DA neurons. Therefore, without undermining the importance of L-DOPA therapy in PD, there is an urgent need to acquire a deeper understanding of the pathogenesis of PD in order to identify new molecular targets for potential therapeutic intervention. The cause of SNpc DA neurodegeneration in PD is currently unknown. We do know, however, that dysfunction in complex I of the mitochondrial respiratory chain is an important feature of PD-related neurodegeneration. We have previously shown that activation of the mitochondria-dependent apoptotic pathway is instrumental in the neuronal degeneration associated with disruption of mitochondrial respiration caused by complex I deficiency in experimental PD (Perier et al., PNAS, 2005). Complex I blockade, however, is not the actual executioner but rather sensitises neurons to mitochondria-dependent apoptosis through oxidative damage and activation of the pro-apoptotic Bcl-2 family member Bax (Perier et al., PNAS, 2005). However, it remains unknown (i) how complex I deficiency leads to Bax activation and (ii) whether pharmacological targeting of Bax may attenuate SNpc DA neurodegeneration in PD. In this project, we unravelled the molecular mechanisms leading to Bax activation in an experimental mouse model of PD based on the administration of the parkinsonian neurotoxin MPTP and demonstrate that pharmacological inhibition of Bax activation protects against PD-related dopaminergic neurodegeneration in this model. Here is a brief summary of the main results obtained: 1. The tumor suppressor p53 is activated and mediates the transcriptional induction of Bax in the ventral midbrain of MPTP-intoxicated mice. 2. Despite p53 being activated, BH3-only molecules Puma and Noxa, two of p53 downstream targets necessary for Bax mitochondrial translocation, do not play a role in MPTP-induced dopaminergic neurodegeneration. 3. Genetic ablation of p53 in mutant mice attenuates MPTP-induced Bax upregulation, cytochrome c release and apoptotic cell death, resulting in an increased survival of SNpc DA neurons in this experimental model of PD. In contrast, p53 does not influence MPTP-induced Bax mitochondrial translocation. 4. Pro-apoptotic BH3-only protein Bim is activated, in a JNK-dependent manner, in SNpc DA neurons of MPTP-intoxicated mice, where it participates in Bax mitochondrial translocation. Accordingly, genetic ablation of Bim in mutant mice prevents MPTP-related Bax activation, cytochrome c release and apoptotic cell death, resulting in an increased survival of SNpc DA neurons in this experimental model of PD. 5. The pharmacological compounds Bax-inhibiting peptide (BIP) and Humanin (HN), both of which had been previously reported to inhibit Bax activation in vitro, do not attenuate dopaminergic neurodegeneration in MPTP-intoxicated mice. In contrast, a Bax channel inhibitor compound (BCI), is able to inhibit Bax-dependent mitochondrial pore formation and attenuate PD-related dopaminergic neurodegeneration in vivo, both at the level of dopaminergic neuron cell bodies and striatal dopaminergic terminals. Overall our results provide further insights into the pathogenesis of PD by the identification of new molecular targets and pharmaceutical tools of potential therapeutic significance for this disabling, currently incurable, neurological disorder.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз