Abou-Sleiman PM, Muqit MM, Wood NWExpanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci 7:207-219

Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Nature reviews Neuroscience (Impact Factor: 31.43). 04/2006; 7(3):207-19. DOI: 10.1038/nrn1868
Source: PubMed


The quest to disentangle the aetiopathogenesis of Parkinson's disease has been heavily influenced by the genes associated with the disease. The alpha-synuclein-centric theory of protein aggregation with the adjunct of parkin-driven proteasome deregulation has, in recent years, been complemented by the discovery and increasing knowledge of the functions of DJ1, PINK1 and OMI/HTRA2, which are all associated with the mitochondria and have been implicated in cellular protection against oxidative damage. We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease, and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.

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Available from: Miratul M K Muqit, Dec 17, 2013
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    • "There is accumulating evidence from in vitro and in vivo studies suggesting that mitochondrial abnormalities are a common event in PD (Langston et al., 1984; Bindoff et al., 1989; Parker et al., 1989; Abou-Sleiman et al., 2006). "
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    ABSTRACT: Creatine is the substrate for creatine kinase in the synthesis of phosphocreatine (PCr). This energetic system is endowed of antioxidant and neuroprotective properties and plays a pivotal role in brain energy homeostasis. The purpose of this study was to investigate the neuroprotective effect of creatine and PCr against 6-hydroxydopamine (6-OHDA)-induced mitochondrial dysfunction and cell death in rat striatal slices, used as an in vitro Parkinson's model. The possible involvement of the signaling pathway mediated by phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase-3β (GSK3β) was also evaluated. Exposure of striatal slices to 6-OHDA caused a significant disruption of the cellular homeostasis measured as 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction, lactate dehydrogenase release, and tyrosine hydroxylase levels. 6-OHDA exposure increased the levels of reactive oxygen species and thiobarbituric acid reactive substances production and decreased mitochondrial membrane potential in rat striatal slices. Furthermore, 6-OHDA decreased the phosphorylation of Akt (Serine(473)) and GSK3β (Serine(9)). Coincubation with 6-OHDA and creatine or PCr reduced the effects of 6-OHDA toxicity. The protective effect afforded by creatine or PCr against 6-OHDA-induced toxicity was reversed by the PI3K inhibitor LY294002. In conclusion, creatine and PCr minimize oxidative stress in striatum to afford neuroprotection of dopaminergic neurons. © The Author(s) 2014.
    ASN Neuro 10/2014; 6(6). DOI:10.1177/1759091414554945 · 4.02 Impact Factor
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    • "Mutations in PINK1 are the second most common cause of recessive PD (following mutations in the ubiquitin ligase Parkin) and are thought to contribute to 1–8% of familial PD (Kawajiri et al., 2011). Unlike LRRK2, PINK1 mutations reduce kinase activity and cause an atypical form of PD characterized by an early age of onset and slower clinical progression (Abou-Sleiman et al., 2006; Woodroof et al., 2011). "
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    ABSTRACT: Substantial evidence implicates abnormal protein kinase function in various aspects of Parkinson's disease (PD) etiology. Elevated phosphorylation of the PD-defining pathological protein, α-synuclein, correlates with its aggregation and toxic accumulation in neurons, whilst genetic missense mutations in the kinases PTEN-induced putative kinase 1 and leucine-rich repeat kinase 2, increase susceptibility to PD. Experimental evidence also links kinases of the phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways, amongst others, to PD. Understanding how the levels or activities of these enzymes or their substrates change in brain tissue in relation to pathological states can provide insight into disease pathogenesis. Moreover, understanding when and where kinase dysfunction occurs is important as modulation of some of these signaling pathways can potentially lead to PD therapeutics. This review will summarize what is currently known in regard to the expression of these PD-implicated kinases in pathological human postmortem brain tissue.
    Frontiers in Molecular Neuroscience 06/2014; 7:57. DOI:10.3389/fnmol.2014.00057 · 4.08 Impact Factor
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    • "The pathological hallmark of PD is the degeneration of dopaminergic neurons of substantia nigra that project into striatum [1]. The underlying mechanisms of dopaminergic neuronal death in sporadic PD are still uncertain, but mitochondrial dysfunctions, oxidative stress, proteolytic impairment with abnormal accumulation of proteins like alpha-synuclein, and inflammatory reactions are key elements in this complex pathogenesis [1] [2] [3]. Several animal and cell-based experimental models have been widely used to elucidate the mechanism of dopaminergic neuronal death in sporadic "
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    ABSTRACT: Background. The cytotoxic effects of dopamine (DA) on several catecholaminergic cell lines involve DA oxidation products like reactive oxygen species (ROS) and toxic quinones and have implications in the pathogenesis of sporadic Parkinson's disease (PD). However, many molecular details are yet to be elucidated, and the possible nonoxidative mechanism of dopamine cytotoxicity has not been studied in great detail. Results. Cultured SH-SY5Y cells treated with DA (up to 400 μM) or lactacystin (5 μM) or DA (400 μM) plus N-acetylcysteine (NAC, 2.5 mM) for 24 h are processed accordingly to observe the cell viability, mitochondrial dysfunctions, oxidative stress parameters, proteasomal activity, expression of alpha-synuclein gene, and intracellular accumulation of the protein. DA causes mitochondrial dysfunction and extensive loss of cell viability partially inhibited by NAC, potent inhibition of proteasomal activity marginally prevented by NAC, and overexpression with accumulation of intracellular alpha-synuclein partially preventable by NAC. Under similar conditions of incubation, NAC completely prevents enhanced production of ROS and increased formation of quinoprotein adducts in DA-treated SH-SY5Y cells. Separately, proteasomal inhibitor lactacystin causes accumulation of alpha-synuclein as well as mitochondrial dysfunction and cell death. Conclusions. DA cytotoxicity includes both oxidative and nonoxidative modes and may involve overexpression and accumulation of alpha-synuclein as well as proteasomal inhibition.
    Parkinson's Disease 04/2014; 2014:878935. DOI:10.1155/2014/878935 · 2.01 Impact Factor
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