Objective: Investigate the associated metabolic changes in PD via a comprehensive metabolic analysis with a focus on phenylalanine (dopamine precursor) metabolism and its impact on the dopaminergic, adrenergic, and melatonergic pathways. Moreover, we examined hypothesis that phenylalanine metabolism in PD may be shifted toward trans-cinnamate (a phenylalanine metabolite) production, affecting the levels of critical neurotransmitters such as tyrosine.

Background: PD is stamped by the dopaminergic neuron loss. Although the dopamine metabolism has been extensively studied, the role of phenylalanine metabolism remains unclear. Earlier studies have reported alterations in phenylalanine, tyrosine, and phenylalanine hydroxylase (PAH) levels in PD ^(1,2,3), proposing a link between phenylalanine metabolism and disease progression. However, the underlying mechanisms and metabolic shifts remain unexplored.

Method: Plasma samples from 27 PD patients, 18 controls, and 8 high-risk individuals (with genetic risk or family history) underwent non-targeted metabolomics analysis. Metabolites analyzed included trans-cinnamate, phenylalanine, tyrosine, dopamine (DA), norepinephrine (NE), and 3-hydroxyanthranilic acid (3HAA), linking phenylalanine and tryptophan metabolism. Principal component analysis used K-means clustering. After testing normality, Welch’s t-test compared metabolite signal intensities, followed by multiple comparison tests.

Results: The results exhibited higher levels of trans-cinnamate in PD patients compared to controls, while lower levels of phenylalanine, tyrosine, DA, NE, 3HAA, tryptamine, and melatonin were detected in PD patients (Fig.1 & 2) ⁽⁴⁾.

Conclusion: Our study highlights the metabolic changes in the phenylalanine metabolism in PD. The elevated levels of trans-cinnamate in PD patients suggest a novel possible shift in the metabolism of phenylalanine towards trans-cinnamate via L-phenylalanine ammonia lyase instead of tyrosine via PAH, signifying downstream impacts on the production of neurotransmitters, including DA, NE, and melatonin, and a possible involving in the neurodegenerative procedures in PD (Fig.2 & 3). A validation study is currently underway to confirm these findings in a larger cohort.

Previously presented in AD/PD Conference in March 2024.

Figure 1

Figure 2

Figure 3

References: 1. Braham, J., Sarova-Pinhas, I., Crispin, M., Golan, R., Levin, N., and Szeinberg, A. (1969). Oral phenylalanine and tyrosine tolerance tests in parkinsonian patients. BMJ 2 (5656), 552–555. doi:10.1136/bmj.2.5656.552.
2. Hirayama, M., Tsunoda, M., Yamamoto, M., Tsuda, T., and Ohno, K. (2016). Serum tyrosine-to-phenylalanine ratio is low in Parkinson’s disease. J. Parkinson’s Dis. 6 (2), 423–431. doi:10.3233/JPD-150736.
3. Rawlings, L., Turton, L., Mitchell, S. C., and Steventon, G. B. (2019). Drug S-oxidation and phenylalanine hydroxylase: a biomarker for neurodegenerative susceptibility in Parkinson’s disease and amyotrophic lateral sclerosis. Drug Metabolism Personalized Ther. 34 (2),/j/dmdi.2019.34.issue-2/dmpt-2018-0038/dmpt-2018-0038.xml. doi:10.1515/dmpt-2018-0038.
4. Shebl, N., El-Jaafary, S., Saeed, A. A., Elkafrawy, P., El-Sayed, A., Shamma, S., Elnemr, R., Mekky, J., Mohamed, L. A., Kittaneh, O., El-Fawal, H., Rizig, M., & Salama, M. (2024). Metabolomic profiling reveals altered phenylalanine metabolism in Parkinson’s disease in an Egyptian cohort. Frontiers in molecular biosciences, 11, 1341950. https://doi.org/10.3389/fmolb.2024.1341950.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/metabolomic-profiling-in-an-egyptian-cohort-reveals-altered-phenylalanine-metabolism-and-suggests-a-role-for-trans-cinnamate-in-parkinson-disease/