Abstract
Parkinson's disease (PD) is a common, late-onset movement disorder with selective degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Although the neurotoxin 6-hydroxydopamine (6-OHDA) has been used to induce progressive degeneration of DA neurons in various animal models of PD, the precise molecular pathway and the impact of anti-apoptotic treatment on this neurodegeneration are less understood. Following a striatal injection of 6-OHDA, we observed atrophy and progressive death of DA neurons in wild-type mice. These degenerating DA neurons never exhibited signs of apoptosis (i.e., caspase-3 activation and cytoplasmic release of cytochrome C), but rather show nuclear translocation of apoptosis-inducing factor (AIF), a hallmark of regulated necrosis. However, mice with genetic deletion of the proapoptotic gene Bax (Bax-KO) exhibited a complete absence of 6-OHDA-induced DA neuron death and nuclear translocation of AIF, indicating that 6-OHDA-induced DA neuronal death is mediated by Bax-dependent AIF activation. On the other hand, DA neurons that survived in Bax-KO mice exhibited marked neuronal atrophy, without significant improvement of PD-related behavioral deficits. These findings suggest that anti-apoptotic therapy may not be sufficient for PD treatment, and the prevention of Bax-independent neuronal atrophy may be an important therapeutic target.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders characterized by a progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN), which leads to the typical symptoms, including tremor, rigidity, and bradykinesia [1,2,3,4]
The reduction of tyrosine hydroxylase (TH)+ neurons was evident in 2 weeks after 6-OHDA injection, and at 6 weeks, approximately 50% (VTA) and 70% (SN) of TH+ neurons disappeared in WT mice (Fig. 1K, L)
We found that most Bax-KO DA neurons survived for up to 2 weeks after 6-OHDA treatment, these surviving neurons appeared to have reduced TH expression, similar to WT mice (Fig. 1E vs. 1F and 1H vs. 1I, insets)
Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders characterized by a progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN), which leads to the typical symptoms, including tremor, rigidity, and bradykinesia [1,2,3,4]. Neuronal apoptosis is mediated by the activation of the proapoptotic Bcl-2 family protein Bax, and mitochondrial translocation of Bax triggers the release of cytochrome C into the cytosol, which promotes apoptosome formation and subsequent caspase-3 activation [5,6]. Genetic deletion of the pro-apoptotic gene Bax (Bax-KO), or overexpression of the anti-apoptotic gene Bcl-2, suppressed MPTP-induced DA neuronal death [11,12]. These lines of evidence implicate apoptosis, other lines of evidence suggest the involvement of other types of cell death, such as autophagy and necrosis [13,14,15,16]
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