Parkinson’s Disease Master Regulators on Substantia Nigra and Frontal Cortex and Their Use for Drug Repositioning

Vargas, Daiani Machado de; Bastiani, Marco Antônio De; Parsons, Richard B.; Klamt, Fábio

doi:10.1007/s12035-020-02203-x

Cited by 8 publications

(5 citation statements)

References 156 publications

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“…Little is known about the SLC30A9 function, although it has recently been linked to Covid-19 because of strong co-purification of SLC30A9 with SARS-CoV-2 proteins (supplementary data in [64]). Furthermore, SLC30A9 has recently been identified as a master regulator of Parkinson's pathogenesis [65]. Given the central role of mitochondria in Parkinson's pathology [66] and the emerging role of zinc in this process [67], the evidence of SLC30A9 in the mitochondria suggests a novel contributing factor to Parkinson's disease.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Kowalczyk

Gbadamosi

Kolor

et al. 2021

Biochemical Journal

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Recent advances in genome sequencing have led to the identification of new ion and metabolite transporters, many of which have not been characterized. Due to the variety of subcellular localizations, cargo and transport mechanisms, such characterization is a daunting task, and predictive approaches focused on the functional context of transporters are very much needed. Here we present a case for identifying a transporter localization using evolutionary rate covariation (ERC), a computational approach based on pairwise correlations of amino acid sequence evolutionary rates across the mammalian phylogeny. As a case study, we find that poorly characterized transporter SLC30A9 (ZnT9) coevolves with several components of the mitochondrial oxidative phosphorylation chain, suggesting mitochondrial localization. We confirmed this computational finding experimentally using recombinant human SLC30A9. SLC30A9 loss caused zinc mishandling in the mitochondria, suggesting that under normal conditions it acts as a zinc exporter. We therefore propose that ERC can be used to predict the functional context of novel transporters and other poorly characterized proteins.

show abstract

Section: Discussionmentioning

confidence: 99%

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Kowalczyk

Gbadamosi

Kolor

et al. 2021

Biochemical Journal

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show abstract

“…Little is known about the SLC30A9 function, although it has recently been linked to Covid-19 because of strong co-purification of SLC30A9 with SARS-CoV-2 proteins (supplementary data in (Gordon et al, 2020)). Furthermore, SLC30A9 has recently been identified as a master regulator of Parkinson's pathogenesis (Vargas et al, 2021). Given the central role of mitochondria in Parkinson's pathology (Trinh et al, 2021) and the emerging role of zinc in this process (Park et al, 2014), the evidence of SLC30A9 in the mitochondria suggests a novel contributing factor to Parkinson's disease.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Kowalczyk

Gbadamosi

Kolor

et al. 2021

Preprint

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Recent advances in genome sequencing have led to the identification of new ion and metabolite transporters, many of which have not been characterized. Due to the variety of subcellular localizations, cargo and transport mechanisms, such characterization is a daunting task, and predictive approaches focused on the functional context of transporters are very much needed. Here we present a case for identifying a transporter localization using evolutionary rate covariation (ERC), a computational approach based on pairwise correlations of amino acid sequence evolutionary rates across the mammalian phylogeny. As a case study, we find that poorly characterized transporter SLC30A9 (ZnT9) uniquely and prominently coevolves with several components of the mitochondrial oxidative phosphorylation chain, suggesting mitochondrial localization. We confirmed this computational finding experimentally using recombinant human SLC30A9. SLC30A9 loss caused zinc mishandling in the mitochondria, suggesting that under normal conditions it acts as a zinc exporter. We therefore propose that ERC can be used to predict the functional context of novel transporters and other poorly characterized proteins.

show abstract

“…However, it is worth noting that for drug repositioning means, none of the cellular models analyzed have emerged as a statistically reliable source for lung clinical data. As final considerations, we emphasize that the in silico approach described in this report has already been successfully applied in the context of several other diseases ( De Bastiani et al, 2018 ; De Bastiani and Klamt, 2019 ; Vargas et al, 2021 , 2018 ), although comparison of in vitro and clinical models should be further studied to optimize translational medicine.…”

Section: Discussionmentioning

confidence: 99%

A comparative study of COVID-19 transcriptional signatures between clinical samples and preclinical cell models in the search for disease master regulators and drug repositioning candidates

et al. 2023

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Parkinson’s Disease Master Regulators on Substantia Nigra and Frontal Cortex and Their Use for Drug Repositioning

Cited by 8 publications

References 156 publications

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

A comparative study of COVID-19 transcriptional signatures between clinical samples and preclinical cell models in the search for disease master regulators and drug repositioning candidates

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