Purine molecules in Parkinson's disease: Analytical techniques and clinical implications

Seggern, Molly Von; Szarowicz, Carlye A.; Swanson, Matthew A; Cavotta, Samantha; Pike, Schuyler T.; Lamberts, Jennifer T.

doi:10.1016/j.neuint.2020.104793

Cited by 8 publications

(7 citation statements)

References 49 publications

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“…ATIC is the last enzyme in the de novo purine biosynthesis pathway, which plays important roles in various diseases including neurological diseases (Jaeken & Van den Berghe, 1984; Marie et al , 2004; Pedley & Benkovic, 2017; Ramond et al , 2020; Joy et al , 2022). Alterations in purine metabolism have strong correlations with PD progression (Johansen et al , 2009; Garcia‐Esparcia et al , 2015; Havelund et al , 2017; LeWitt et al , 2017; Von Seggern et al , 2020; Danau et al , 2022). Particularly, metabolomic profiling in LRRK2 patients revealed significant aberrations of the major molecules in the purine pathway (Johansen et al , 2009).…”

Section: Discussionmentioning

confidence: 99%

Regulation of LRRK2 mRNA stability by ATIC and its substrate AICAR through ARE‐mediated mRNA decay in Parkinson's disease

Liu

Zhu

et al. 2023

The EMBO Journal

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Mutations in LRRK2 are the most common genetic causes of Parkinson's disease (PD). While the enzymatic activity of LRRK2 has been linked to PD, previous work has also provided support for an important role of elevated LRRK2 protein levels, independent of enzymatic activity, in PD pathogenesis. However, the mechanisms underlying the regulation of LRRK2 protein levels remain unclear.Here, we identify a role for the purine biosynthesis pathway enzyme ATIC in the regulation of LRRK2 levels and toxicity. AICAr, the precursor of ATIC substrate, regulates LRRK2 levels in a celltype-specific manner in vitro and in mouse tissue. AICAr regulates LRRK2 levels through AUF1-mediated mRNA decay. Upon AICAr treatment, the RNA binding protein AUF1 is recruited to the AUrich elements (ARE) of LRRK2 mRNA leading to the recruitment of the decapping enzyme complex DCP1/2 and decay of LRRK2 mRNA. AICAr suppresses LRRK2 expression and rescues LRRK2-induced dopaminergic neurodegeneration and neuroinflammation in PD Drosophila and mouse models. Together, this study provides insight into a novel regulatory mechanism of LRRK2 protein levels and function via LRRK2 mRNA decay that is distinct from LRRK2 enzymatic functions.

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Section: Discussionmentioning

confidence: 99%

Regulation of LRRK2 mRNA stability by ATIC and its substrate AICAR through ARE‐mediated mRNA decay in Parkinson's disease

Liu

Zhu

et al. 2023

The EMBO Journal

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“…α-Synuclein is a primary trigger of the immune response in PD [ 99 ] and may activate both the innate and adaptive immune system since the degree of microglial activation directly correlates with α-synuclein load in post-mortem brains [ 99 ]. Purine metabolism is also overrepresented in the "LFC > 0" gene set, with levels of urate and other purines known to correlate with PD severity [ 100 ]. Regarding purine-ribose dysregulation observed in females, a reported link to microglial activation (neuroinflammation) and neurodegeneration [ 9 ] could inspire the design of specific therapeutic strategies in male and female PD patients.…”

Section: Discussionmentioning

confidence: 99%

Unveiling sex-based differences in Parkinson's disease: a comprehensive meta-analysis of transcriptomic studies

et al. 2022

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Background In recent decades, increasing longevity (among other factors) has fostered a rise in Parkinson's disease incidence. Although not exhaustively studied in this devastating disease, the impact of sex represents a critical variable in Parkinson’s disease as epidemiological and clinical features differ between males and females. Methods To study sex bias in Parkinson’s disease, we conducted a systematic review to select sex-labeled transcriptomic data from three relevant brain tissues: the frontal cortex, the striatum, and the substantia nigra. We performed differential expression analysis on each study chosen. Then we summarized the individual differential expression results with three tissue-specific meta-analyses and a global all-tissues meta-analysis. Finally, results from the meta-analysis were functionally characterized using different functional profiling approaches. Results The tissue-specific meta-analyses linked Parkinson’s disease to the enhanced expression of MED31 in the female frontal cortex and the dysregulation of 237 genes in the substantia nigra. The global meta-analysis detected 15 genes with sex-differential patterns in Parkinson’s disease, which participate in mitochondrial function, oxidative stress, neuronal degeneration, and cell death. Furthermore, functional analyses identified pathways, protein–protein interaction networks, and transcription factors that differed by sex. While male patients exhibited changes in oxidative stress based on metal ions, inflammation, and angiogenesis, female patients exhibited dysfunctions in mitochondrial and lysosomal activity, antigen processing and presentation functions, and glutamic and purine metabolism. All results generated during this study are readily available by accessing an open web resource (http://bioinfo.cipf.es/metafun-pd/) for consultation and reuse in further studies. Conclusions Our in silico approach has highlighted sex-based differential mechanisms in typical Parkinson Disease hallmarks (inflammation, mitochondrial dysfunction, and oxidative stress). Additionally, we have identified specific genes and transcription factors for male and female Parkinson Disease patients that represent potential candidates as biomarkers to diagnosis.

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“…α-synuclein is a primary trigger of the immune response in PD [99] and may activate both the innate and adaptive immune system since the degree of microglial activation directly correlates with α-synuclein load in post-mortem brains [99]. Purine metabolism is also overrepresented in the "LFC > 0" gene set, with levels of urate and other purines known to correlate with PD severity [100]. Regarding purine-ribose dysregulation observed in females, a reported link to microglial activation (neuroin ammation) and neurodegeneration [9] could inspire the design of speci c therapeutic strategies in male and female PD patients.…”

Section: Sn Sex-based Functional Pro Lingmentioning

confidence: 99%

Unveiling Sex-based Differences in Parkinson's Disease: A Comprehensive Meta-analysis of Transcriptomic Studies

López‐Cerdán

Andreu

Hidalgo

et al. 2022

Preprint

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Background:In recent decades, increasing longevity (among other factors) has fostered a rise in Parkinson's disease incidence. Although not exhaustively studied in this devastating disease, the impact of sex represents a critical variable in Parkinson’s Disease as epidemiological and clinical features differ between males and females. Methods: To study sex bias in Parkinson’s Disease, we conducted a systematic review to select sex-labeled transcriptomic data from three relevant brain tissues: the frontal cortex, the striatum, and the substantia nigra. We performed differential expression analysis on each study chosen. Then we summarized the individual differential expression results with three tissue-specific meta-analyses and a global all-tissues meta-analysis. Finally, results from the meta-analysis were functionally characterized using different functional profiling approaches. Results: The tissue-specific meta-analyses linked Parkinson’s Disease to the enhanced expression of MED31 in the female frontal cortex and the dysregulation of 237 genes in the substantia nigra. The global meta-analysis detected 15 genes with sex-differential patterns in Parkinson’s disease, which participate in mitochondrial function, oxidative stress, neuronal degeneration, and cell death. Furthermore, functional analyses identified pathways, protein-protein interaction networks, and transcription factors that differed by sex. While male patients exhibited changes in oxidative stress based on metal ions, inflammation, and angiogenesis, female patients exhibited dysfunctions in mitochondrial and lysosomal activity, antigen processing and presentation functions, and glutamic and purine metabolism. All results generated during this study are readily available by accessing an open web resource (http://bioinfo.cipf.es/metafun-pd/) for consultation and reuse in further studies. Conclusions: Our in-silico approach has highlighted sex-based differential mechanisms in typical Parkinson Disease hallmarks (inflammation, mitochondrial dysfunction, and oxidative stress). Additionally, we have identified specific genes and transcription factors for male and female Parkinson Disease patients that represent potential candidates as biomarkers to diagnosis.

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Purine molecules in Parkinson's disease: Analytical techniques and clinical implications

Cited by 8 publications

References 49 publications

Regulation of LRRK2 mRNA stability by ATIC and its substrate AICAR through ARE‐mediated mRNA decay in Parkinson's disease

Regulation of LRRK2 mRNA stability by ATIC and its substrate AICAR through ARE‐mediated mRNA decay in Parkinson's disease

Unveiling sex-based differences in Parkinson's disease: a comprehensive meta-analysis of transcriptomic studies

Unveiling Sex-based Differences in Parkinson's Disease: A Comprehensive Meta-analysis of Transcriptomic Studies

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