Parkinson’s disease (PD), is the most common movement disorder and is characterized primarily by the loss of dopaminergic neurons in the substantia nigra pars compacta leading to a dopamine deficiency in the striatum. The loss of regulation of the basal ganglia neurones accounts for the motor symptoms which include bradykinesia, hypokinesia, rigidity, resting tremour and postural instability. In addition to these typical motor symptoms, various none motor features may also develop, such as autonomic dysfunction, sleep disturbances, depression and cognitive impairment. A pathological trait of sporadic PD is the presence of proteinaceous deposits within the neuronal perykarya called Lewy bodies and neuronal processes called Lewy neurites, which are mainly composed of ?-synuclein, ubiquitin, neurofilaments and molecular chaperones 1.
Little is known about the aetiopathogenesis of PD. The most common sporadic form of PD seems to be a complex multifactorial disorder with variable contributions of environmental factors and genetic susceptibility. Aging is the most important risk factor, thus with increasing average life expectancy the incidence and prevalence of PD will rise considerably in the near future. The major stepforward in PD research was the discovery of genes which are responsible for the familial forms of the disease, ?- synuclein, LRRK2 parkin, PINK1 and DJ-1 2-9. Both sporadic and the monogenetic forms share important clinical, pathological and biochemical features, such as the progressive demise of dopaminergic neurones in the substantia nigra. Thus, any insights into the function and dysfunction of PD-associated gene products will help to uncover the underlying mechanisms leading to neuronal cell death. Evidence in the literature now indicates that PD-associated genes directly or indirectly impinge on mitochondrial integrity, thereby providing a link to pathophysiological alterations observed in sporadic PD 2-9.
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both the upper motor neurons and lower motor neurones. Average disease duration is about three years, but it can vary significantly. Death usually results from compromise of the respiratory muscles. The prevalence of individuals with ALS is roughly 4-8:100,000 10 and is similar to the number of newly diagnosed individuals each year.
Like PD little is known about the aetiology of sporadic ALS with reports of environmental causes of ALS including mercury, manganese and farming products (fertilizers, insecticides, herbicides) and dietary factors 11. Genetics also plays a role in the disease pathology with an estimated 10% of individuals with ALS having at least one other affected family member. The enzyme superoxide dismutase (SOD) is particularly associated with ALS. SOD1 pathogenic variants account for 20% of all familial ALS and approximately 3% of sporadic ALS 12, 13. Thus, the aetiology of sporadic ALS is now thought to be multifactorial with a combination of mitochondrial dysfunction, oxidative stress, glutamate excitotoxicity and environmental triggers being proposed as biomarkers of disease susceptibility.
Xenobiotic metabolism and degenerative neurological disease
Since 1988 publications have been appearing in the literature indicating that sporadic PD and ALS are associated with abnormalities in the S-oxidation of S-carboxymethyl-L-cysteine (SCMC) 14-17. No real advances were reported after 2003 and like the ring of power in Tolkein’s Lord of the Rings triology “… some things that should not have been forgotten were lost. History became legend. Legend became myth.” The story of the S-oxidation polymorphism and PD and ALS slowly faded with time. However, following the identification of the enzyme responsible for the sulfur oxygenation of SCMC in rat, mouse, HepG2 cells, humans and cDNA expressed phenylalanine hydroxylase proteins new life has been given to this story 18-28.
It is proposed that the enzyme known as phenylalanine hydroxylase (phenylalanine monooxygenase, PAH, EC. 126.96.36.199) whose classical function is the conversion of phenylalanine to tyrosine, has other metabolic roles within the body. Although phenylalanine is the preferred substrate the enzyme has been shown to oxidise several other compounds including the drug, S-carboxymethyl-L-cysteine. Whilst most allelic variants of PAH adequately metabolise phenylalanine, thereby avoiding any clinical consequence, they are unable to effectively metabolise these secondary substrates. Poor sulphoxidation of S-carboxymethyl-L-cysteine has been reported as a risk factor for developing PD and ALS, the drug being a presumed metabolic ‘probe’ for PAH allelic variants. It is proposed that these allelic variants of PAH, themselves capable of maintaining sufficient phenylalanine metabolism, are unable to metabolise other as yet unknown ‘toxic substances’, and it is the accumulation of subsequent ‘toxic insults’ that assist in the development of these neurological problems.
The S-oxidation polymorphism
A re-evaluation of the S-oxidation polymorphism in controls, PD and ALS subjects has been undertaken to investigate the association of PAH with these diseases. The collated data now re-evaluated has been published previously in various forms 14-17, 28, 29 but never has the data been looked at in its totallity. This resulted in the analysis of 300 healthy controls, 401 disease controls (these included neither degenerative neurological disease subjects nor subjects taking medication). Typical diagnoses in these two groups were lumbar disc disease, benign intracranial hypertension, multiple sclerosis and those in whom no organic disease was discovered. Other in-patients studied had no neurological disease but had diverse general medical illness and were chosen because they were receiving no medication, 175 PD (receiving no medication) and 105 ALS subjects (receiving no medication). The results can be seen in Tables 1, 2 and Figure 1). There were no differences between the healthy controls and disease controls with respect to the statistical analysis of the % total urinary recovered, % sulfides recovered, % S-oxides recovered and S-oxidation Index (Table 1, P>0.05, Kruskal-Wallis One Way Analysis of Variance on Ranks for all variables data not shown). Thus, the results from the heathy controls and the diseased controls was combined to give a control population of 701 subjects. When the statistical analysis of the Controls, PD and ALS subjects was evaluated for male versus female differences with respect to the variables, % total urinary recovered, % sulfides recovered, % S-oxides recovered and S-oxidation Index no significant differences were found (Table 1, P>0.05, Kruskal-Wallis One Way Analysis of Variance on Ranks for all variables data not shown). Thus, the data from male and female subjects within each subject group (Controls, PD and ALS) were combined. The results of the S-oxidation phenotyping study in the Control, PD and ALS subjects can be seen in Tables 1, 2 and Figure 1. There were no significant differences in the total recovery of drug related material (SCMC plus sulfide and S-oxide metabolites) between the Controls (51.3% (17.3%-98.2%)), PD (47.9% (22.9%-94.2%)) and ALS subjects (48. 5% (28.8%-90.8%) P>0.05, Kruskal-Wallis One Way Analysis of Variance on Ranks. However, the % recovery of sulfides was significantly higher in the PD (44.5% (9.3%-90.1%)) and ALS (45.0% (18.9%-90.1%)) subjects compared to the Controls (36.7% (9.3-93.9%)) P