MitoNEET (CISD1) Knockout Mice Show Signs of Striatal Mitochondrial Dysfunction and a Parkinson's Disease Phenotype.
*aging; *Disease Models; *drug discovery; *mitochondrial dysfunction; *mitoNEET; Animal; Animals; Corpus Striatum/*metabolism/*pathology; Inbred C57BL; Iron-Binding Proteins/genetics/*metabolism; Knockout; Male; Membrane Proteins/genetics/*metabolism; Mice; Mitochondria/*metabolism/*pathology; Parkinson Disease/*metabolism/pathology
Mitochondrial dysfunction is thought to play a significant role in neurodegeneration observed in Parkinson's disease (PD), yet the mechanisms underlying this pathology remain unclear. Here, we demonstrate that loss of mitoNEET (CISD1), an iron-sulfur containing protein that regulates mitochondrial bioenergetics, results in mitochondrial dysfunction and loss of striatal dopamine and tyrosine hydroxylase. Mitochondria isolated from mice lacking mitoNEET were dysfunctional as revealed by elevated reactive oxygen species (ROS) and reduced capacity to produce ATP. Gait analysis revealed a shortened stride length and decreased rotarod performance in knockout mice, consistent with the loss of striatal dopamine. Together, these data suggest that mitoNEET KO mice exhibit many of the characteristics of early neurodegeneration in PD and may provide a novel drug discovery platform to evaluate compounds for enhancing mitochondrial function in neurodegenerative disorders.
Geldenhuys Werner J; Benkovic Stanley A; Lin Li; Yonutas Heather M; Crish Samuel D; Sullivan Patrick G; Darvesh Altaf S; Brown Candice M; Richardson Jason R
ACS chemical neuroscience
2017
2017-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1021/acschemneuro.7b00287" target="_blank" rel="noreferrer noopener">10.1021/acschemneuro.7b00287</a>
Exploring Adenosine Receptor Ligands: Potential Role in the Treatment of Cardiovascular Diseases.
Humans; Animals; Protein Binding; Signal Transduction; atherosclerosis; *Drug Discovery; *Ligands; Adenosine/metabolism; cardiac death; Cardiovascular Diseases/drug therapy/metabolism; Cardiovascular System/metabolism; Hydrogen Bonding; Molecular Structure; myocardial infarction; Structure-Activity Relationship; vascular tone; Receptors; Models; Molecular; Purinergic P1/*chemistry/*metabolism
Cardiovascular diseases remain the number one diseases affecting patients' morbidity and mortality. The adenosine receptors are G-protein coupled receptors which have been of interest for drugs target for the treatment of multiple diseases ranging from cardiovascular to neurological. Adenosine receptors have been connected to several biological pathways affecting the physiology and pathology of the cardiovascular system. In this review, we will cover the different adenosine receptor ligands that have been identified to interact with adenosine receptors and affect the vascular system. These ligands will be evaluated from clinical as well as medicinal chemistry perspectives with more emphasis on how structural changes in structure translate into ligand potency and efficacy. Adenosine receptors represent a novel therapeutic target for development of treatment options treating a wide variety of diseases, including vascular disease and obesity.
Geldenhuys Werner J; Hanif Ahmad; Yun June; Nayeem Mohammed A
Molecules (Basel, Switzerland)
2017
2017-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3390/molecules22060917" target="_blank" rel="noreferrer noopener">10.3390/molecules22060917</a>