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

  • Lucinda Rawlings , Laura Turton , Stephen C. Mitchell and Glyn B. Steventon EMAIL logo



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.


Meta-analysis of previously published investigations into the S-oxidation polymorphism together with new subject data was evaluated.


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).


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.


GBS would like to thank Prof. A.C. Williams, Department of Neurology, Queens Elizabeth Hospital, Birmingham, UK, for providing the PD and ALS patients and Dr. Rosemary Waring, School of Biochemistry, University of Birmingham, UK, for SCMC bioanalysis support. The investigation was supported by the Wellcome Trust, UK, Parkinson’s Disease Society, UK and the Motor Neurone Disease Association, UK.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


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Received: 2018-12-04
Accepted: 2019-02-11
Published Online: 2019-04-02

© 2019 Walter de Gruyter GmbH, Berlin/Boston

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