Drug S-oxidation and phenylalanine hydroxylase: a biomarker for neurodegenerative susceptibility in Parkinson’s disease and amyotrophic lateral sclerosis

Abstract

Background The S-oxidation of S-carboxymethyl-L-cysteine has been reported previously to be a biomarker of disease susceptibility in Parkinson’s disease and amyotrophic lateral sclerosis. In the present investigation, the original observations have been extended and confirmed. Methods Meta-analysis of previously published investigations into the S-oxidation polymorphism together with new subject data was evaluated. Results The incidence of the poor metaboliser phenotype (no urinary recovery of S-oxide metabolites) was found to be 3%–7% within healthy and non-neurological disease populations, whereas 38% of the Parkinson’s disease subjects and 39% of the amyotrophic lateral sclerosis group were phenotyped as poor metabolisers. The consequent odds risk ratio of developing Parkinson’s disease was calculated to be 33.8 [95% confidence interval (CI), 13.3–86.1] and for amyotrophic lateral sclerosis was 35.2 (95% CI, 13.0–85.1). Conclusions The possible involvement of the enzyme responsible for this S-oxidation biotransformation reaction, phenylalanine hydroxylase, should be further investigated to elucidate its potential role in the mechanism(s) of toxicity in susceptible individuals displaying these diseases. The “Janus hypothesis,” possibly explaining why phenylalanine hydroxylase is a biomarker of neurodegenerative disease susceptibility, together with the general theme that this concept may apply to many other hitherto unsuspected enzyme systems, is presented.

Metabolomic profiling reveals altered phenylalanine metabolism in Parkinson’s disease in an Egyptian cohort

“…Additionally, another study found that the tyrosine/phenylalanine ratio in PD patients is lower than that in controls ( Hirayama et al, 2016 ), this suggests that the metabolic pathway of phenylalanine (through PAH) in PD may shift to another one that does not end by tyrosine. Indeed, recently PD patients showed lower activity in their PAH enzyme ( Steventon and Mitchell, 2018 ; Rawlings et al, 2019 ). All these studies support our hypothesis that the metabolism of phenylalanine in PD patients is altered via the following mechanisms: 1) reduction of PAH activity, which results in metabolizing phenylalanine through the PAL metabolic pathways, thus, reducing the production of tyrosine, and, subsequently, dopamine and norepinephrine; 2) enhancing PAL activity with the resultant increase in the production of trans-cinnamate and ammonia.…”

Protective Effect of Medicinal Plants on Neuron Degeneration Diseases and Controversial Predictive Diagnosis

“…Also, integrins are play important role pathophysiology of many brain diseases, such as epilepsy, and consider a potential target for the discovery of new drugs for neurological disorders [11,12] different biomarkers are currently being studied in Alzheimer disease and other neurodegeneration diseases such as cerebrospinal fluid (CSF) Aβ, tau, phosphorylated tau and the other neuronal proteins, PET tracers for Aβ, tau and glucose uptake, and MR measures of brain diseases [13][14][15]. Interestingly, phenylalanine hydroxylase could also be a biomarker of neurodegenerative disease [16] (Figure 2). The only promising in prevention and delay neurodegenerative diseases are many herbal plants that have been studied like Nigella sativa (Khazdair, 2015), moringa olifera [17] and many Plants-derived natural products used in the treatment of neurological diseases [18].…”