Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson's disease

Abstract

Dysfunction of mitochondrial complex I is associated with a wide spectrum of neurodegenerative disorders, including Parkinson's disease (PD). In rodents, inhibition of complex I leads to degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc), as seen in PD, through activation of mitochondriadependent apoptotic molecular pathways. In this scenario, complex I blockade increases the soluble pool of cytochrome c in the mitochondrial intermembrane space through oxidative mechanisms, whereas activation of pro-cell death protein Bax is actually necessary to trigger neuronal death by permeabilizing the outer mitochondrial membrane and releasing cytochrome c into the cytosol. Activation of Bax after complex I inhibition relies on its transcriptional induction and translocation to the mitochondria. apoptosis ͉ Bax ͉ Bim ͉ complex I ͉ 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine C omplex I deficiency impairs mitochondrial respiration and is associated with a wide spectrum of neurodegenerative disorders, including Parkinson's disease (PD). Reduced complex I activity is found in both autopsy brain tissues and platelets of patients affected with sporadic PD (1-3). Furthermore, complex I inhibitors, such as 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP), reproduce some of the clinical and neuropathological hallmarks of PD in monkeys and humans, including degeneration of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) (4). Studies in rodents and human postmortem PD samples indicate that SNpc DA neurodegeneration linked to complex I deficiency occurs, at least in part, through activation of mitochondria-dependent apoptotic molecular pathways (5, 6). Complex I blockade, however, is not the actual executioner but rather sensitizes neurons to mitochondria-dependent apoptosis through oxidative damage and activation of the proapoptotic Bcl-2 family member Bax (6).Activation of Bax relies, in most instances, not only on its transcriptional induction but also on its posttranslational modification. The latter results in Bax translocation and insertion into the mitochondrial outer membrane, thereby eliciting cytochrome c release and activation of the caspase cascade, which ultimately causes cell death (7). Both transcriptional and posttranslational activation of Bax have been observed in the SNpc of MPTPintoxicated mice (6,8) and PD patients (9, 10). Furthermore, genetic ablation of Bax in mutant mice prevents mitochondriadependent apoptotic SNpc DA cell death caused by complex I inhibition with MPTP (6, 8). In contrast, both Bid and Bak, which cooperate with Bax to initiate mitochondria-dependent apoptosis in response to activation of cell-surface death receptors, are probably dispensable for MPTP-induced neuronal death (11, 12). Bax thus governs SNpc DA cell death linked to PD-related complex I deficiency. However, the molecular mechanisms of Bax activation after complex I blockade remain unknown.Although Bax transcriptional induction associated with complex I blockade might be media...

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

“…[28][29][30] Bim, a member of pro-apoptotic BH3-only proteins, promotes cell death of CNS neurons including SNpc dopaminergic neurons by binding to Bcl-2 family pro-survival proteins and facilitating activation of Bax/Bak, which subsequently induces mitochondrial release of cytochrome-c and caspase-9 activation. 31 By interacting with its cell surface receptor Fas, FasL promotes neuronal apoptosis via activating caspase-8.…”

“…[29][30][31][32] Therefore, it was hypothesized that (G2019S) LRRK2 causes degeneration of SNpc dopaminergic neurons in (G2019S) LRRK2 mice by promoting the formation of active caspase-9, caspase-8, and caspase-3. In accordance with this hypothesis, protein level of cleaved active caspase-9, active caspase-8, or active caspase-3 was greatly increased in the SN of 12-month-old (G2019S) LRRK2 mice (Figure 7a).…”

The kinase domain of mitochondrial PINK1 faces the cytoplasm

“…Western blot analysis was performed as described in ref. 40 by using the primary antibodies raised against PINK1175-250 (Novus), PINK1 N4/15 (NeuroMab), HA (Santa Cruz Biotechnology), Myc (Abcam), TOM20 (BD Biosciences, Franklin Lakes, NJ), and ␤-actin (Sigma Aldrich). Band quantification was performed by using Scion Image software, and all immunoblot data were from three independent experiments.…”

“…These procedures were performed as described in ref. 40. The purity of each fraction was determined by using anti-HSP60 and anti-HSP70 antibodies.…”

Iromycins from Streptomyces sp. and from synthesis: New inhibitors of the mitochondrial electron transport chain

“…10 Synthetic MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 2) and the plant-derived rotenone (3) are now regularly used in cell cultures and model studies of Parkinson's disease. 10,11 The enormous structural diversity of known inhibitors of complex I, which also includes microbial myxalamids (e.g., 4) 12 and piericidins (e.g., 5) 13 as well as the fungal verticipyrone (6), 14 has led to attempts to classify these compounds into three fundamental types based on their presumed different modes of inhibition in the ubiquinone redox cycle and thus, different binding sites. 6 However, current hypotheses of the inhibitor binding domain suggest a common large binding pocket, which is constructed by multiple subunits and has several, partially overlapping binding positions for the structurally diverse inhibitor molecules.…”