The neuroprotective enzyme CYP2D6 increases in the brain with age and is lower in Parkinson's disease patients

Mann, Amandeep; Miksys, Sharon; Gaedigk, Andrea; Kish, Stephen J.; Mash, Deborah C.; Tyndale, Rachel F.

doi:10.1016/j.neurobiolaging.2011.08.014

Cited by 72 publications

(47 citation statements)

References 43 publications

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“…We searched for enriched pathways in the PDgset using ToppGene and found 44 significant enrichment pathways for PD (Table 1). Consistent with previous studies [46], several pathways related to metabolism, e.g., drug metabolism-cytochrome P450 (ranked 1st in Table 1) and metabolism of xenobiotics by cytochrome P450 (ranked 3rd in Table 1), were enriched in PDgset. Also, neurotransmitter-related pathways were identified, such as dopaminergic synapse, serotonergic synapse, tyrosine metabolism, etc., all of which were closely related to signal transduction.…”

Section: Pathway Enrichment Analysis In Pdgsetsupporting

confidence: 88%

Network and Pathway-Based Analyses of Genes Associated with Parkinson’s Disease

Pan

Ying

et al. 2016

Mol Neurobiol

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Parkinson's disease (PD) is a major neurodegenerative disease influenced by both genetic and environmental factors. Although previous studies have provided insights into the significant impacts of genetic factors on PD, the molecular mechanism underlying PD remains largely unclear. Under such situation, a comprehensive analysis focusing on biological function and interactions of PD-related genes will provide us valuable information to understand the pathogenesis of PD. In the current study, by reviewing the literatures deposited in PUBMED, we identified 242 genes genetically associated with PD, referred to as PD-related genes gene set (PDgset). Functional analysis revealed that biological processes and biochemical pathways related to neurodevelopment, metabolism, and immune system were enriched in PDgset. Then, pathway crosstalk analysis indicated that the enriched pathways could be grouped into two modules, with one module consisted of pathways mainly involved in neuronal signaling and another in immune response. Further, based on a global human interactome, we found that PDgset tended to have more moderate degree compared with cancer-related genes. Moreover, PD-specific molecular network was inferred using Steiner minimal tree algorithm and some potential related genes associated with PD were identified. In summary, by using network- and pathway-based methods to explore pathogenetic mechanism underlying PD, results from our work may have important implications for understanding the molecular mechanism underlying PD. Also, the framework proposed in our current work can be used to infer pathological molecular network and genes related to a specific disease.

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Section: Pathway Enrichment Analysis In Pdgsetsupporting

confidence: 88%

Network and Pathway-Based Analyses of Genes Associated with Parkinson’s Disease

Pan

Ying

et al. 2016

Mol Neurobiol

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“…A post mortem study of brains of individuals with Parkinson disease showed that CYP2D6 extensive metabolizers had about 50% lower brain levels of CYP2D6 than their age-matched, nondiseased controls. 26 This reduction was seen in various regions, including those unaffected by Parkinson disease, such as the cerebellum and hippocampus, supporting the hypothesis that lower brain CYP2D6 levels seen in individuals with Parkinson disease may be a predisposing factor. Together, these data support a contributing role for lower brain CYP2D6 in the increased risk for Parkinson disease, likely through modulation of local neurotoxin metabolism.…”

Section: Neurotoxicitymentioning

confidence: 53%

“…In humans, the brain CYP2D6 enzyme level is low at birth, increases gradually with age, and is highest in adults older than 65 years, 26 whereas hepatic CYPs increase quickly after birth to adult levels and remain constant with age. 27,28 This suggests that for some centrally acting drugs, older adults may respond differently than younger adults.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450–mediated drug metabolism in the brain

Miksys

Tyndale

2013

J Psychiatry Neurosci

116

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“…Several studies suggest that microsomal CYP2D6, supported by microsomal NPR, has a protective role through production of the inactive metabolites PTP and MPTP-OH, implying that higher microsomal CYP2D6 levels render a protective effect (53). In this regard, both WT and ϩSRP CYP2D6-expressing cells showed significantly less toxicity following MPTP treatment despite containing substantial albeit lower levels of mitochondrial CYP2D6 (Fig.…”

Section: Discussionmentioning

confidence: 92%