Multifunctional tellurium molecule protects and restores dopaminergic neurons in Parkinson’s disease models Benjamin Sredni * ,1 ,2 , Revital Geffen-Aricha † ,1 , Wenzhen Duan ‡ , Michael Albeck § , Frances Shalit * , Harry M. Lander || , Noa Kinor † , Ortal Sagi * , Amnon Albeck § , Sigal Yosef § , Miri Brodsky * , Dvora Sredni-Kenigsbuch ¶ , Tali Sonino * , Dan L. Longo # , Mark P. Mattson 1 and Gal Yadid † ,1 * CAIR Institute, The Mina and Everard Goodman Faculty of Life Sciences, † Leslie Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center; § Department of Chemistry, ¶ Interdisciplinary Department, Bar-Ilan University, Ramat-Gan, Israel. ‡ Laboratory of Neurosciences and # Laboratory of Immunology, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA; and || Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, USA 2 Correspondence: CAIR Institute, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Keren Hayessod St., Ramat Gan, Israel. E-mail: srednib@mail.biu.ac.il In Parkinson’s disease (PD) dopaminergic neurons in the substantia nigra (SN) become dysfunctional and many ultimately die. We report that the tellurium immunomodulating compound ammonium trichloro(dioxoethylene-O,O’-)tellurate(AS101) protects dopaminergic neurons and improves motor function in animal models of PD. It is effective when administered systemically or by direct infusion into the brain. Multifunctional activities of AS101 were identified in this study. These were mainly due to the peculiar Tellur IV -thiol chemistry of the compound, which enabled the compound to interact with cysteine residues on both inflammatory and apoptotic caspases, resulting in their inactivation. Conversely, its interaction with a key cysteine residue on p21 ras , led to its activation, an obligatory activity for AS101-induced neuronal differentiation. Furthermore, AS101 inhibited IL-10, resulting in up-regulation of GDNF in the SN. This was associated with activation of the neuroprotective kinases Akt and mitogen-activated protein kinases, and up-regulation of the antiapoptotic protein Bcl-2. Inhibition of caspase-1 and caspase-3 activities were associated with decreased neuronal death and inhibition of IL-1ß. We suggest that, because multiple mechanisms are involved in the dysfunction and death of neurons in PD, use of a multifunctional compound, exerting antiapoptotic, anti-inflammatory, and neurotrophic-inducing capabilities may be potentially efficacious for the treatment of PD.—Sredni B., Geffen R., Duan W., Albeck M., Shalit F., Lander H., Kinor N., Sagi O., Albeck A., Yosef S., Brodsky M., Sredni-Kenigsbuch D., Sonino T., Longo D., Mattson M., Yadid G. Multifunctional tellurium molecule protects and restores dopaminergic neurons in Parkinson’s disease models. Key Words: neuroprotection • apoptosis • inflammation • cytokines • neurotrophic

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