S‐Nitrosylation in Parkinson's Disease and Related Neurodegenerative Disorders
Introduction
Parkinson's disease (PD) is one of the most common neurodegenerative diseases that is characterized by motor dysfunction such as bradykinesia, rest tremor, gait abnormalities, and postural instability. James Parkinson first described the disease in his “An Essay on the Shaking Palsy” published in 1817. There are at least 500,000 people affected by PD with increasing new cases being reported annually in United States. PD is mostly sporadic, but genetically linked cases are also found. For instance, mutations in α‐synuclein, parkin, DJ‐1, and PINK1 have been linked to rare familial forms of PD (Greenamyre and Hastings, 2004). Pathological studies have revealed that a selective loss of dopaminergic neurons and the presence of Lewy bodies (proteinaceous cytoplasmic inclusions) in the substantia nigra pars compacta (SNc) are common in patients with PD. The exact pathogenic mechanism of PD is not fully understood, but both genetic and environmental factors are believed to contribute to the disease. The contribution of environmental factors is best demonstrated by the finding that some drug addicts who had accidentally injected an impurity of “synthetic heroin” later developed severe parkinsonism (Langston 1983, Langston 1999). The impurity that caused PD in those people was later found to be 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) (Langston 1983, Langston 1999). Studies have shown that oxidative free radicals generated in the mitochondria by MPP+ (metabolite of MPTP) are responsible for dopaminergic neuronal toxicity (Zhang et al., 2000b). In fact, oxidative stress has long been considered a prime suspect in the pathogenesis of PD. This notion is supported by postmortem pathological studies that mitochondria complex I dysfunction, increased nitrotyrosine immunoreactivity, reduced glutathione and ferritin levels, increased lipid peroxidation, and increased levels of iron are common in patients with PD (Chung et al., 2003). However, the underlying detailed mechanism of how oxidative stress can cause the selective dopaminergic cell death still remains to be elucidated.
Section snippets
Nitrosative Stress and Parkinson's Disease
One of the major contributors of oxidative stress in PD is believed to be nitric oxide (NO) (Ischiropoulos 2003, Jenner 2003). NO is the most studied bioactive gas molecule and is involved in a wide spectrum of biological process. Excessive production of NO leads to cellular toxicity (Dawson and Dawson, 1998). In PD, various studies have pointed to the involvement of NO in the pathogenesis (Ischiropoulos 2003, Jenner 2003). For instance, increased nitrotyrosine immunoreactivity and nitrated
Photolysis Chemiluminescence
The method was first developed to measure S‐nitrosothiols in mammalian plasma (Stamler et al., 1992) and later shown to be able to distinguish different biologically relevant derivatives of NO species (Alpert et al., 1997). The basic theory in this method is to use ultraviolet (UV) radiation to cleave the NO from the S‐NO bonds, and the released NO is measured using chemiluminescence method. The system consists of a high‐performance liquid chromatographic (HPLC)/GC system, a photolysis chamber
S‐Nitrosylation and PD
Because of the strong evidence that NO is one of the major players in the pathogenesis of PD, we investigated the possible involvement of S‐nitrosylation in regulating the function of parkin, a familial PD–related protein, with a combination of the methods described earlier. Parkin is an E3 ligase in the ubiquitin pathway, which selectively attaches ubiquitin on specific substrates (Chung 2003, Shimura 2000, Zhang 2000a), and it is linked to autosomal recessive juvenile parkinsonism (Kitada et
Concluding Remarks
The understanding of the pathogenic mechanism of PD has improved dramatically in the past decade. The rapid advancement has been fueled by investigating the mechanisms of MPTP dopaminergic toxicity and advances in human genetics, which enabled the identification genes that are linked to familial PD. One of the fundamental questions is whether the pathogenesis of the more common sporadic form of PD converges in a common pathway with MPTP‐induced parkinsonism and the familial linked PD. Evidence
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