Fighting Bax: towards a Parkinson's disease therapy.

Parkinson's disease (PD) affects ∼1% of people that are over 60 years old. It has long been known that this disease is caused by a severe reduction in striatal dopamine production. This effect is caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the loss of the associated projecting fibers in the striatum. These neuronal losses translate physiologically into muscular tremors, rigidity, akinesia, postural instability, cognitive impairment and are frequently associated with depression. Pathophysiological symptoms and neurological lesions similar to those found in PD can be reproduced in mammals by injection of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This PD model was used by Vila et al.1xBax ablation prevents dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Vila, M et al. Proc. Natl. Acad. Sci. USA. 2001; 98: 2837–2842Crossref | PubMed | Scopus (229)See all References1 to study the role of the pro-apoptotic signal Bax in the MPTP-induced death of neurons in wild type and mutant Bax-deficient mice.In adult wild-type mice the authors detected abundant intracellular amounts of Bax in neurons of the SNpc. Bax expression levels were further shown to regulate SNpc neuronal death because apoptosis was decreased in Bax-deficient mice in a gene dose dependent manner. Significantly, in MPTP-injected mice Bax expression levels were increased in regions specifically affected by the neurodegeneration processes. Furthermore, the time-course of Bax upregulation followed the kinetics of apoptotic-induced neuronal death. MPTP treatment was also shown to induce a dramatic reduction in levels of the anti-apoptotic factor Bcl-2 in the ventral midbrain (which includes the SNpc). Thus, increasing the pressure for neuronal apoptosis as a result of decreased Bcl-2 neutralization of Bax activity. Relevant to PD, Bax deficient mutant mice were shown to be resistant to MPTP neurotoxicity. The authors showed an almost complete inhibition of dopaminergic neuron loss on MPTP administration to Bax knockout animals. Additionally, the dopaminergic nerve terminals in the striatum and dopamine production by neurons in the SNpc were preserved in these animals.These experiments show that Bax is an important regulator of apoptotic neurodegeneration and that Bax plays a pivotal role in the destruction of dopamine-producing neurons in a mouse model of PD. In regard to actual therapeutic tools, the data presented in this paper make Bax an attractive target for novel therapeutic interventions aimed to limiting PD progression. Additionally, manipulating events downstream of Bax might yet provide a more specific approach to target this disease. However, in spite of the almost complete survival of neurons in Bax-deficient mice treated with MPTP, dopamine production is still markedly reduced in these animals. This indicates that there is more to the MPTP-induced symptoms than simply neuronal death, and raises questions as to the dopamine levels that are sufficient to prevent clinical disease. This study represents a significant step forward in our understanding of PD and proposes potential targets for therapeutic intervention.