Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson’s disease model
TL;DR: The combination of microtubule depolymerization and the accumulation of cytosolic dopamine and reactive oxygen species selectively affects survival of dopaminergic neurons.
Abstract: Mitochondrial complex I dysfunction is regarded as underlying dopamine neuron death in Parkinson’s disease models. However, inactivation of the Ndufs4 gene, which compromises complex I activity, does not affect the survival of dopamine neurons in culture or in the substantia nigra pars compacta of 5-wk-old mice. Treatment with piericidin A, a complex I inhibitor, does not induce selective dopamine neuron death in either Ndufs4+/+ or Ndufs4−/− mesencephalic cultures. In contrast, rotenone, another complex I inhibitor, causes selective toxicity to dopamine neurons, and Ndufs4 inactivation potentiates this toxicity. We identify microtubule depolymerization and the accumulation of cytosolic dopamine and reactive oxygen species as alternative mechanisms underlying rotenone-induced dopamine neuron death. Enhanced rotenone toxicity to dopamine neurons from Ndufs4 knockout mice may involve enhanced dopamine synthesis caused by the accumulation of nicotinamide adenine dinucleotide reduced. Our results suggest that the combination of disrupting microtubule dynamics and inhibiting complex I, either by mutations or exposure to toxicants, may be a risk factor for Parkinson’s disease.
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TL;DR: The role of mitochondria in the etiopathogenesis of Parkinson's disease has been investigated in this paper, based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models.
Abstract: Neurons are critically dependent on mitochondrial integrity based on specific morphological, biochemical, and physiological features. They are characterized by high rates of metabolic activity and need to respond promptly to activity-dependent fluctuations in bioenergetic demand. The dimensions and polarity of neurons require efficient transport of mitochondria to hot spots of energy consumption, such as presynaptic and postsynaptic sites. Moreover, the postmitotic state of neurons in combination with their exposure to intrinsic and extrinsic neuronal stress factors call for a high fidelity of mitochondrial quality control systems. Consequently, it is not surprising that mitochondrial alterations can promote neuronal dysfunction and degeneration. In particular, mitochondrial dysfunction has long been implicated in the etiopathogenesis of Parkinson's disease (PD), based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Substantial progress towards understanding the role of mitochondria in the disease process has been made by the identification and characterization of genes causing familial variants of PD. Studies on the function and dysfunction of these genes revealed that various aspects of mitochondrial biology appear to be affected in PD, comprising mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control.
526 citations
Cites background from "Loss of mitochondrial complex I act..."
...Ndufs4-deficient DA neurons are even more sensitive to rotenone, and complex I-independent mechanisms have been reported to contribute to the toxicity of rotenone, such as microtubule depolymerization (Ren et al, 2005; Choi et al, 2011)....
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...…lack functional Ndufs4, a gene encoding a subunit implicated in assembly and function of complex I. Ndufs4 KO mice show neuronal degeneration in the cerebellum, olfactory bulb, and vestibular nuclei, whereas DA neurons are not affected (Kruse et al, 2008; Quintana et al, 2010; Choi et al, 2011)....
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...…striatal dopamine homeostasis may be caused by a reduced vesicular uptake of dopamine due to ATP deficiency followed by enhanced cytosolic dopamine metabolism, suggesting that impaired dopamine release may be an early consequence of mitochondrial impairment (Choi et al, 2011; Sterky et al, 2012)....
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TL;DR: How epidemiological data may help to validate a specific model with data linking a lower risk of developing PD with nutritional/consumption habits or with a specific chronic drug therapy is discussed.
Abstract: Animal experimentation in the Parkinson's disease (PD) field is a classic example of how the use of animal models to study diseases can have a significant impact on human health. Among the different neurotoxin-based animal models of PD that are presently available, the 6-hydroxydopamine (6-OHDA) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models have been established and validated as useful models for the development of therapeutic strategies aimed to treat motor symptoms and to study alterations of the basal ganglia that occur in this disease. The 6-OHDA rat model and the MPTP primate model have contributed enormously to translate animal experimentation into clinical practice, including pharmacological treatments and deep brain stimulation of the subthalamic nucleus. These models, along with the MPTP mouse model, are helping to elucidate the pathogenic mechanism of neurodegeneration in PD. The roles of oxidative stress, apoptosis, mitochondrial dysfunction, inflammation, and impairment of the protein degradation pathways have also come under careful consideration thanks to these models. The more recently developed paraquat and rotenone rodent models are also contributing to our understanding of neuronal cell death. However, none of the neuroprotective strategies that have worked in the pre-clinical stage have thus far been successfully translated to a clinical setting to treat PD patients. At the same time, the lack of any effective neuroprotective strategy for PD is preventing the validation of any one particular model as a screening tool for such neuroprotective strategies. Therefore, it seems that we are trapped in a vicious circle that casts doubt on the suitability of the neurotoxin-based models for this purpose. Here, we discuss how epidemiological data may help to validate a specific model with data linking a lower risk of developing PD with nutritional/consumption habits or with a specific chronic drug therapy.
438 citations
Additional excerpts
...5) (Marshall and Himes, 1978; Brinkley et al., 974; Choi et al., 2011)....
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TL;DR: Clinical and pathological evidence is presented to support the hypothesis that PD starts in the gut and spreads via trans-synaptic cell-to-cell transfer of pathology through the sympathetic and parasympathetic nervous systems to the substantia nigra and the CNS.
Abstract: Parkinson disease (PD) follows a defined clinical pattern, and a range of nonmotor symptoms precede the motor phase. The predominant early nonmotor manifestations are olfactory impairment and constipation. The pathology that accompanies these symptoms is consistent with the Braak staging system: α-synuclein in the dorsal motor nucleus of the vagus nerve, the olfactory bulb, the enteric nervous system (ENS) and the submandibular gland, each of which is a gateway to the environment. The neuropathological process that leads to PD seems to start in the ENS or the olfactory bulb and spreads via rostrocranial transmission to the substantia nigra and further into the CNS, raising the intriguing possibility that environmental substances can trigger pathogenesis. Evidence from epidemiological studies and animal models supports this hypothesis. For example, in mice, intragastric administration of the pesticide rotenone can almost completely reproduce the typical pathological and clinical features of PD. In this Review, we present clinical and pathological evidence to support the hypothesis that PD starts in the gut and spreads via trans-synaptic cell-to-cell transfer of pathology through the sympathetic and parasympathetic nervous systems to the substantia nigra and the CNS. We also consider how environmental factors might trigger pathogenesis, and the potential for therapeutically targeting the mechanisms of these initial stages.
419 citations
TL;DR: It is proposed that a new focus on the neurobiology of axons, their molecular pathways of degeneration and growth, will offer novel opportunities for neuroprotection and restoration in the treatment of PD and other neurodegenerative diseases.
Abstract: Parkinson's disease (PD) is the most common neurodegenerative disease of the basal ganglia. Like other adult-onset neurodegenerative disorders, it is without a treatment that forestalls its chronic progression. Efforts to develop disease-modifying therapies to date have largely focused on the prevention of degeneration of the neuron soma, with the tacit assumption that such approaches will forestall axon degeneration as well. We herein propose that future efforts to develop neuroprotection for PD may benefit from a shift in focus to the distinct mechanisms that underlie axon degeneration. We review evidence from human post-mortem studies, functional neuroimaging, genetic causes of the disease and neurotoxin models that axon degeneration may be the earliest feature of the disease, and it may therefore be the most appropriate target for early intervention. In addition, we present evidence that the molecular mechanisms of degeneration of axons are separate and distinct from those of neuron soma. Progress is being made in understanding these mechanisms, and they provide possible new targets for therapeutic intervention. We also suggest that the potential for axon re-growth in the adult central nervous system has perhaps been underestimated, and it offers new avenues for neurorestoration. In conclusion, we propose that a new focus on the neurobiology of axons, their molecular pathways of degeneration and growth, will offer novel opportunities for neuroprotection and restoration in the treatment of PD and other neurodegenerative diseases.
368 citations
References
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TL;DR: PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.
Abstract: Parkinson's disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms; none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular events that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are pivotal to PD pathogenesis. Previously implicated culprits in PD neurodegeneration, mitochondrial dysfunction and oxidative stress, may also act in part by causing the accumulation of misfolded proteins, in addition to producing other deleterious events in dopaminergic neurons. Neurotoxin-based models (particularly MPTP) have been important in elucidating the molecular cascade of cell death in dopaminergic neurons. PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.
4,872 citations
"Loss of mitochondrial complex I act..." refers background in this paper
...The observation that drug abusers accidentally exposed to 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) developed Parkinsonism provided the first evidence for this hypothesis because 1-methyl-4phenylpyridinium (MPP), the toxic metabolite of MPTP, is a mitochondrial complex I inhibitor (Langston et al., 1983; Dauer and Przedborski, 2003)....
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..., 2007a), whose cytotoxicity is largely caused by oxidative stress but is independent of complex I inhibition (Day et al., 1999; Jones and Vale, 2000; Dauer and Przedborski, 2003; Bonneh-Barkay et al., 2005; McCormack et al., 2005; Richardson et al., 2005)....
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TL;DR: It is proposed that this chemical selectively damages cells in the substantia nigra in patients who developed marked parkinsonism after using an illicit drug intravenously.
Abstract: Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.
4,705 citations
TL;DR: It is reported that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity.
Abstract: The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.
3,472 citations
"Loss of mitochondrial complex I act..." refers background in this paper
...Chronic treatment of rats and mice with rotenone, a wellestablished complex I inhibitor, induces many key features of Parkinson’s disease (Betarbet et al., 2000; Sherer et al., 2003b; Inden et al., 2007; Pan-Montojo et al., 2010)....
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1,548 citations
01 Jan 1993
TL;DR: Results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease, which adds further support to the proposition that Parkinson’s disease may be due to an environmental toxin with action(s) similar to those of MPTP.
Abstract: The structure and function of mitochondrial respiratory-chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinson's disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH-ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinson's disease may be due to an environmental toxin with action(s) similar to those of MPTP.
1,313 citations
"Loss of mitochondrial complex I act..." refers background in this paper
...Furthermore, complex I activity is decreased in the substantia nigra, skeletal muscle, and platelets of patients with Parkinson’s disease (Mizuno et al., 1989; Parker et al., 1989; Schapira et al., 1989)....
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