@article {2019, title = {Calpains as mechanistic drivers and therapeutic targets for ocular disease.}, journal = {Trends Mol Med}, volume = {28}, year = {2022}, month = {2022 08}, pages = {644-661}, abstract = {

Ophthalmic neurodegenerative diseases encompass a wide array of molecular pathologies unified by calpain dysregulation. Calpains are calcium-dependent proteases that perpetuate cellular death and inflammation when hyperactivated. Calpain inhibition trials in other organs have faced pharmacological challenges, but the eye offers many advantages for the development and testing of targeted molecular therapeutics, including small molecules, peptides, engineered proteins, drug implants, and gene-based therapies. This review highlights structural mechanisms underlying calpain activation, distinct cellular expression patterns, and in vivo models that link calpain hyperactivity to human retinal and developmental disease. Optimizing therapeutic approaches for calpain-mediated eye diseases can help accelerate clinically feasible strategies for treating calpain dysregulation in other diseased tissues.

}, keywords = {Calcium, Calpain, Cell Death, Humans, Retina}, issn = {1471-499X}, doi = {10.1016/j.molmed.2022.05.007}, author = {Vu, Jennifer T and Wang, Elena and Wu, Jolan and Sun, Young Joo and Velez, Gabriel and Bassuk, Alexander G and Lee, Soo Hyeon and Mahajan, Vinit B} } @article {149, title = {Mutations in prickle orthologs cause seizures in flies, mice, and humans.}, journal = {American journal of human genetics}, volume = {88}, year = {2011}, month = {2011 Feb 11}, pages = {138-49}, abstract = {

Epilepsy is heritable, yet few causative gene mutations have been identified, and thus far no human epilepsy gene mutations have been found to produce seizures in invertebrates. Here we show that mutations in prickle genes are associated with seizures in humans, mice, and flies. We identified human epilepsy patients with heterozygous mutations in either PRICKLE1 or PRICKLE2. In overexpression assays in zebrafish, prickle mutations resulted in aberrant prickle function. A seizure phenotype was present in the Prickle1-null mutant mouse, two Prickle1 point mutant (missense and nonsense) mice, and a Prickle2-null mutant mouse. Drosophila with prickle mutations displayed seizures that were responsive to anti-epileptic medication, and homozygous mutant embryos showed neuronal defects. These results suggest that prickle mutations have caused seizures throughout evolution.

}, keywords = {Animals, Blotting, Western, Brain, Calcium, Carrier Proteins, DNA-Binding Proteins, Drosophila melanogaster, Drosophila Proteins, Embryo, Nonmammalian, Epilepsies, Myoclonic, Female, Heterozygote, Humans, Immunoenzyme Techniques, In Situ Hybridization, Male, Mice, Mice, Knockout, Mutation, Nerve Tissue Proteins, Phenotype, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Seizures, Tumor Suppressor Proteins, Zebrafish, Zebrafish Proteins}, author = {Tao, Hirotaka and Manak, J Robert and Sowers, Levi and Mei, Xue and Kiyonari, Hiroshi and Abe, Takaya and Dahdaleh, Nader S and Yang, Tian and Wu, Shu and Chen, Shan and Fox, Mark H and Gurnett, Christina and Montine, Thomas and Bird, Thomas and Shaffer, Lisa G and Rosenfeld, Jill A and McConnell, Juliann and Madan-Khetarpal, Suneeta and Berry-Kravis, Elizabeth and Griesbach, Hilary and Saneto, Russell P and Scott, Matthew P and Antic, Dragana and Reed, Jordan and Boland, Riley and Ehaideb, Salleh N and El-Shanti, Hatem and Mahajan, Vinit B and Ferguson, Polly J and Axelrod, Jeffrey D and Lehesjoki, Anna-Elina and Fritzsch, Bernd and Slusarski, Diane C and Wemmie, John and Ueno, Naoto and Bassuk, Alexander G} } @article {185, title = {Creatine kinase, an ATP-generating enzyme, is required for thrombin receptor signaling to the cytoskeleton.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {97}, year = {2000}, month = {2000 Oct 24}, pages = {12062-7}, abstract = {

Thrombin orchestrates cellular events after injury to the vascular system and extravasation of blood into surrounding tissues. The pathophysiological response to thrombin is mediated by protease-activated receptor-1 (PAR-1), a seven-transmembrane G protein-coupled receptor expressed in the nervous system that is identical to the thrombin receptor in platelets, fibroblasts, and endothelial cells. Once activated by thrombin, PAR-1 induces rapid and dramatic changes in cell morphology, notably the retraction of growth cones, axons, and dendrites in neurons and processes in astrocytes. The signal is conveyed by a series of localized ATP-dependent reactions directed to the actin cytoskeleton. How cells meet the dynamic and localized energy demands during signal transmission is unknown. Using the yeast two-hybrid system, we identified an interaction between PAR-1 cytoplasmic tail and the brain isoform of creatine kinase, a key ATP-generating enzyme that regulates ATP within subcellular compartments. The interaction was confirmed in vitro and in vivo. Reducing creatine kinase levels or its ATP-generating potential inhibited PAR-1-mediated cellular shape changes as well as a PAR-1 signaling pathway involving the activation of RhoA, a small G protein that relays signals to the cytoskeleton. Thrombin-stimulated intracellular calcium release was not affected. Our results suggest that creatine kinase is bound to PAR-1 where it may be poised to provide bursts of site-specific high-energy phosphate necessary for efficient receptor signal transduction during cytoskeletal reorganization.

}, keywords = {Adenosine Triphosphate, Animals, Base Sequence, Calcium, Creatine Kinase, Cytoskeleton, Oligonucleotides, Antisense, Rats, Receptor, PAR-1, Receptors, Thrombin, Signal Transduction, Two-Hybrid System Techniques}, author = {Mahajan, V B and Pai, K S and Lau, A and Cunningham, D D} }