The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of protein inclusions (Lewy bodies) are the pathological hallmarks of Parkinson’s disease (PD). PD is triggered by genetic alterations, environmental/occupational exposures and aging. However, the exact molecular mechanisms linking these PD risk factors to neuronal dysfunction are still unclear. Alterations in redox homeostasis and bioenergetics (energy failure) are thought to be central components of neurodegeneration that contribute to the impairment of important homeostatic process in dopaminergic cells such as protein quality control mechanisms, neurotransmitter release/metabolism, axonal transport of vesicles and cell survival. Importantly, both bioenergetics and redox homeostasis are coupled to neuro-glial central carbon metabolism. We and others have recently established a link between the alterations in central carbon metabolism induced by PD risk factors, redox homeostasis and bioenergetics and their contribution to the survival/death of dopaminergic cells. In this review, we focus on the link between metabolic dysfunction, energy failure and redox imbalance in PD, making an emphasis in the contribution of central carbon (glucose) metabolism. The evidence summarized here strongly supports the consideration of PD as a disorder of cell metabolism.

These findings indicate that blockade of NF-kappaB induces apoptosis and is an important factor in the development of OFT during cardiogenesis. However, it remains unknown which members of the Rel family are relevant in this process.

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Even though the molecular mechanisms by which lead induces toxicity and cancer have been intensely studied for many years, its carcinogenic mechanisms are not well understood yet. Several possible mechanisms have been examined to gain understanding on the carcinogenic properties of lead, which include mitogenesis, alteration of gene expression, and oxidative damage, among others. The aim of the present study was to explore the induction of oxidative damage at low lead concentrations using human embryonic hepatic cells WRL-68. Our results showed induction of reactive oxygen species, changes in the superoxide dismutase and catalase activity, as well as an induction of lipidperoxidation and DNA damage. However, after 5 weeks of exposure, these alterations returned to their basal levels. These results taking together indicate that at low concentrations, lead is able to establish an oxidative stress scenario; however under optimal antioxidant defense the oxidative scenario could be abolished through an adaptative process.

Several possible mechanisms have been examined to gain an understanding on the carcinogenic properties of lead, which include among others, mitogenesis, alteration of gene expression, oxidative damage, and inhibition of DNA repair. The aim of the present study was to explore if low concentrations of lead, relevant for human exposure, interfere with Ape1 function, a base excision repair enzyme, and its role in cell transformation in Balb/c-3T3. Lead acetate 5 and 30 μM induced APE1 mRNA and upregulation of protein expression. This increase in mRNA expression is consistent throughout the chronic exposure. Additionally, we also found an impaired function of Ape1 through molecular beacon-based assay. To evaluate the impact of lead on foci formation, a Balb/c-3T3 two-step transformation model was used. Balb/c-3T3 cells were pretreated 1 week with low concentrations of lead before induction of transformation with n-methyl-n-nitrosoguanidine (MNNG) (0.5 μg/mL) and 12-O-tetradecanoylphorbol-13-acetate (TPA) (0.1 μg/mL) (a classical two-step protocol). Morphological cell transformation increased in response to lead pretreatment that was paralleled with an increase in Ape1 mRNA and protein overexpression and an impairment of Ape1 activity and correlating with foci number. In addition, we found that lead pretreatment and MNNG (transformation initiator) increased DNA damage, determined by comet assay. Our data suggest that low lead concentrations (5, 30 μM) could play a facilitating role in cellular transformation, probably through the impaired function of housekeeping genes such as Ape1, leading to DNA damage accumulation and chromosomal instability, one of the most important hallmarks of cancer induced by chronic exposures.

Exposure to lead in environmental and occupational settings continues to be a serious public health problem. At environmentally relevant doses, two mechanisms may underlie lead exposition-induced genotoxicity, disruption of the redox balance and an interference with DNA repair systems. The aim of the study was to evaluate the ability of lead exposition to induce impaired function of Ape1 and its impact on DNA repair capacity of workers chronically exposed to lead in a battery recycling plant. Our study included 53 participants, 37 lead exposed workers and 16 non-lead exposed workers. Lead intoxication was characterized by high blood lead concentration, high lipid peroxidation and low activity of delta-aminolevulinic acid dehydratase (δ-ALAD). Relevantly, we found a loss of DNA repair capacity related with down-regulation of a set of specific DNA repair genes, showing specifically, for the first time, the role of Ape1 down regulation at transcriptional and protein levels in workers exposed to lead. Additionally, using a functional assay we found an impaired function of Ape1 that correlates with high blood lead concentration and lipid peroxidation. Taken together, these data suggest that occupational exposure to lead could decrease DNA repair capacity, inhibiting the function of Ape1, as well other repair genes through the regulation of the ZF-transcription factor, promoting the genomic instability.

Dopaminergic neuronal cell loss in the substantia nigra pars compacta (SNpc) is considered the pathological hallmark of Parkinson’s disease (PD). Since the early 1990s, oxidative stress has been suggested to exert a causative role in the loss of dopaminergic cells. Post-mortem brain sample analyses have reported an increased accumulation of oxidized proteins, nucleic acids and lipids in PD brains. In this chapter, we will provide an introductory overview of reactive oxygen/nitrogen species, antioxidants, and oxidative modification to biomolecules, and the pathogenic mechanisms involved in the alteration of redox homeostasis that occurs in PD. We will also discuss the intrinsic properties of SNpc dopaminergic neurons that make them vulnerable to neurodegeneration. Energy failure and oxidative stress in PD are linked primarily to impaired mitochondria function (ETC), and both phenomena are expected to synergistically act to promote neuronal dysfunction and neurodegeneration. The high energy demands that SNpc DAergic neurons have to maintain neuronal homeostasis and excitability, and the pro-oxidant environment (iron/neuromelanin and dopamine content) are characteristics that make them primary targets for mitochondrial dysfunction.

Proteostasis is defined as the integrated mechanisms within cells that control protein biogenesis, folding, trafficking and degradation. The integrity of the proteome is essential for cellular homeostasis, function and survival and is continuously challenged under both physiological and pathological conditions. Cells have evolved a complex and hierarchical array of processes called protein quality control mechanisms to ensure protein integrity that include chaperones and protein sorting/segregation and degradation pathways. Protein quality control starts even before protein synthesis and continues throughout their ‘lifespan’. Accumulation of misfolded protein aggregates is a hallmark in Parkinson’s disease (PD). The loss of dopaminergic neurons in the substantia nigra is linked to the presence of intraneuronal inclusions called Lewy bodies (LBs). Alterations in protein quality control mechanisms involved in protein folding and clearance of misfolded protein aggregates are linked to the pathogenesis of PD. In this chapter, we will review the proposed mechanisms by which PD risk factors (aging, genetics and environmental exposures) promote protein misfolding and aggregation and impair protein quality control mechanisms. Special emphasis will be placed in the role of oxidative stress in the dysfunction in the chaperone network, the ubiquitin-proteasome (UPS) and the autophagosome-lysosome system in PD.