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Animal Results with Calcium-Reducing Immunosuppressant Suggest Possibly Major Progress on Parkinson’s Disease

Parkinson's disease, which has stricken such notable figures as actor Michael J. Fox, heavyweight boxing champion Muhammad Ali, and painter Salvador Dalí, could be closer to a cure, thanks to a scientist who has apparently been able to eliminate the disease’s neurological effects with the use of an immunosuppressant. Responsible for the scientific finding is Dr. Gabriela Caraveo Piso, a researcher at the Whitehead Institute for Biomedical Research in the United States in the laboratory of world-renowned scientist Dr. Susan Lindquist (http://lindquistlab.wi.mit.edu/). Dr. Caraveo discovered that the role of calcium as an intracellular messenger can become lethal to brain cells when in high concentration. Her findings were published online on March 23, 2015 in the Spanish-language journal Investigacion y Desarrollo. Neurological diseases called synucleinopathies, such as Parkinson's, are characterized by the aggregation of alpha-synuclein protein. This action triggers a series of events such as the rise in intracellular calcium leading to over-activation of the enzyme calcineurin. This in turn removes phosphates (intracellular communication paths) to alter their functions and kill cells. Dr. Caraveo, a biologist graduated from the National Autonomous University of Mexico (UNAM), sought to nip this problem, after performing a series of analyses in yeast, worms, and neurons of mice, and finding that by reducing the levels of activation of calcineurin, without eliminating it completely, the cells survived. By modifying the activation of calcineurin, contact with NFAT protein (nuclear factor of activated T-cells, a generic name for a family of transcription factors important to the immune respone) is cut out, and the communication to actin cytoskeletal rearrangements is redirected, which is responsible for cell morphology, thereby reducing failure in the motor function in animal models of Parkinson said Dr. Caraveo.

To achieve adequate toxicity reduction, the drug tacrolimus was used, which is administered clinically in newly transplanted patients to prevent organ rejection by the immune system. Because calcineurin is also highly expressed in the brain, this immunosuppressant that can cross the blood brain barrier is able to reduce the activation of calcineurin in the brain reducing the toxic symptoms of the disease. But it is important to adjust the dosage, because too much of it completely eliminates the activation of calcineurin preventing stimulation of protective pathways like that for the cytoskeleton leading to cell death.

"The dosage of the drug (tacrolimus), also called FK506, I propose, is well below the level of the immunosuppressants, which allows my work to have immediate treatment of neurological diseases characterized by the aggregation of alpha-synuclein as therapeutic implications as the Parkinson’s disease," explained Dr. Caraveo, a specialist in neurosciences.

In healthy people, cells are able to regulate the amount of intracellular calcium; the problem is when there are neurological diseases such as Parkinson's disease, the element is accumulated, becomes toxic, and kills many neurons including dopaminergic neurons, responsible for implementing the motor functions.

According to preclinical results with tacrolimus, pathologies associated to Parkinson's disease decreased in rodent models. The next step is to start human trials to test its effectiveness and safety as an alternative treatment that could even act as a cure.

[Press release] [Investigacion y Desarrollo abstract]