Dr. Kuldip Dave and Debi,
Thank you for your informative post, I hope you stay in touch. I have always thought that organ transplant recipients had to take anti-rejection drugs for life? In the case of the paper below, it seems the authors have found that there is a therapeutic range where this type of drugs will keep a-synuclein regulated at a healthy level. It may be that a smaller amount of these drugs could be taken lessening side effects?
http://www.pnas.org/content/111/34/E3544.full
Surprisingly, however, both deletion and overexpression of CN increased toxicity in the HiTox strain (
Fig. 2 A and B). One explanation for these apparently contradictory results is that an intermediate level of CN activation is protective against α-syn, whereas either too much or too little is detrimental.
Significance
Ca2+ homeostasis is indispensable for the well being of all living organisms. Ca2+ homeostasis is disrupted by α-synuclein (α-syn), whose misfolding plays a major role in neurodegenerative diseases termed synucleinopathies, such as Parkinson disease. We report that α-syn can induce sustained and highly elevated levels of cytoplasmic Ca2+, thereby activating a calcineurin (CN) cascade that results in toxicity. CN is a highly conserved Ca2+–calmodulin (CaM)-dependent phosphatase critical for sensing Ca2+ concentrations and transducing that information into cellular responses. Limiting, but not eliminating, the availability of CaM, CN and/or CN substrates directly with genetic or pharmacological tools shifts the α-syn–induced CN cascade to a protective mode. This has mechanistic implications for CN's activity and provides a therapeutic venue for the treatment of synucleinopathies.