Oxidative Stress in Parkinson's Disease: A Mechanism of Pathogenic and Therapeutic Significance

By Chun Zhou, Yong Huang, S. Przedborski. Annals of the New York Academy of Sciences, 2008

1,276 citations recorded by the source corpus.

Parkinson's disease (PD) is a common adult‐onset neurodegenerative disorder. Typically PD is a sporadic neurological disorder, and over time affected patients see their disability growing and their quality of life declining. Oxidative stress has been hypothesized to be linked to both the initiation and the progression of PD. Preclinical findings from both in vitro and in vivo experimental models of PD suggest that the neurodegenerative process starts with otherwise healthy neurons being hit by some etiological factors, which sets into motion a cascade of deleterious events. In these models initial molecular alterations in degenerating dopaminergic neurons include increased formation of reactive oxygen species, presumably originating from both inside and outside the mitochondria. In the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of PD, time‐course experiments suggest that oxidative stress is an early event that may directly kill some of the dopaminergic neurons. In this model it seems that oxidative stress may play a greater role in the demise of dopaminergic neurons indirectly by activating intracellular, cell death‐related, molecular pathways. As the neurodegenerative process evolves in the MPTP mouse model, indices of neuroinflammation develop, such as microglial activation. The latter increases the level of oxidative stress to which the neighboring compromised neurons are subjected to, thereby promoting their demise. However, these experimental studies have also shown that oxidative stress is not the sole deleterious factor implicated in the death of dopaminergic neurons. Should a similar multifactorial cascade underlie dopaminergic neuron degeneration in PD, then the optimal therapy for this disease may have to rely on a cocktail of agents, each targeting a different critical component of this hypothesized pathogenic cascade. If correct, this may be a reason why neuroprotective trials using a single agent, such as an antioxidant, have thus far generated disappointing results.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/e66aa939842b6b270fe692d98a4877f73e4742aa

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. M. Valko
2. Mark P. Mattson
3. Christopher M. Dobson
4. M. Mouradian
5. P. Jenner
6. A. Abramov
7. V. Dias
8. E. Junn

In Neurology

1. M. Valko
2. D. Dexter
3. A. Abramov
4. M. Mouradian
5. V. Dias
6. E. Junn
7. Mark P. Mattson
8. Christopher M. Dobson

Citations in the corpus

• Parkinson disease: from pathology to molecular disease mechanisms. (2013, positive): “Starting from the idea of free radical production resulting from increased chemical and enzymatic oxidation of dopamine, through to the mechanism of action of toxins such 6-hydroxydopamine (6-OHDA) and paraquat, to evidence from postmortem and clinical investigations, oxidative stress and the result”
• The Role of Oxidative Stress in Parkinson’s Disease (2013, background): “This is supported by postmortem brain analyses showing increased levels of 4-hydroxyl-2nonenal (HNE), a by-product of lipid peroxidation [8, 9], carbonyl modifications of soluble proteins [10], and DNA and RNA oxidation products 8-hydroxydeoxyguanosine and 8-hydroxy-guanosine [11, 12].”
• Ageing and neuronal vulnerability (2006, background): “Such protein modifications are dramatically increased in vulnerable neurons in AD, PD, HD and AL”
• Glutathione dysregulation and the etiology and progression of human diseases (2009, background): “Environmental toxicants have long been hypothesized to play a dominant role in the sporadic cases of Parkinson's disease, and oxidative stress has been proposed as a major mechanism of cell death in Parkinson's disease (Beal, 2002; Jenner, 2003).”
• Free radicals and antioxidants in normal physiological functions and human disease. (2007, background): “Oxidative stress has been implicated in various pathological conditions involving cardiovascular disease, cancer, neurological disorders, diabetes, ischemia/reperfusion, other diseases and ageing (DalleDonne et al., 2006; Dhalla, Temsah, & Netticadan, 2000; Jenner, 2003; Sayre, Smith, & Perry, 2001)”
• Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors (2008, background): “Increasing evidences suggest that oxidative stress is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer (Lovell and Markesbery, 2006), Parkinson (Jenner, 2003), Creutzfeld–Jacob and prion diseases (Brown, 2005).”
• Oxidative stress and neurodegeneration: where are we now? (2006, background): “…in common (Table 3); impaired mitochondrial function (Reddy and Beal 2005; Zeevalk et al. 2005), increased oxidative damage (Halliwell 1992, 2001; Jenner 2003), defects in the ubiquitin–proteasome system (Stefanis and Keller 2006; McNaught et al. 2001; Ciechanover and Brundin 2003; Keller et al.…”
• Direct Observation of the Interconversion of Normal and Toxic Forms of α-Synuclein (2012, background): “…link between increased levels of oxidative stress and PD (Jenner and Olanow, Cell 149, 1048–1059, May 25, 2012 ª2012 Elsevier Inc. 1053 1998; Jenner, 2003) and the reported specific generation of intracellular reactive oxygen species (ROS) by aggregating proteins implicated in…”