Cysteamine Protects Neurons from Mutant Huntingtin Toxicity¹

Article type: Research Article

Authors: Arbez, Nicolas^{a; *} | Roby, Elaine^{a; c} | Akimov, Sergey^a | Eddings, Chelsy^a | Ren, Mark^a | Wang, Xiaofang^a | Ross, Christopher A.^{a; b; *}

Affiliations: [a] Department of Psychiatry and Behavioral Sciences, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [b] Departments of Neurology, Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [c] Current address: Nuredis, Menlo Park, CA, USA

Correspondence: [*] Correspondence to: Christopher A. Ross, CMSC 8-121, 600 North Wolfe Street, Baltimore, MD 21287, USA. Fax: +1 410 614 0013; E-mail: [email protected] and Nicolas Arbez, CMSC 9-115, 600 North Wolfe Street, Baltimore, MD 21287, USA. [email protected].

Note: [1] This article received a correction notice (Erratum) with the reference: 10.3233/JHD-200003, available at https://content.iospress.com/articles/journal-of-huntingtons-disease/jhd200003.

Abstract: Background:The potential benefit of cysteamine for Huntington’s disease has been demonstrated in HD animal models. Cysteamine and its derivate cystamine were shown to reduce neuropathology and prolong lifespan. Human studies have demonstrated safety, and suggestive results regarding efficacy. Despite all the studies available in vivo, there are only few in vitro studies, and the mechanism of action of cysteamine remains unclear. Objective:The objective of this study is to assess the capacity of cysteamine for neuroprotection against mutant Huntingtin in vitro using cellular models of HD, and to provide initial data regarding mechanism of action. Methods:We tested the neuroprotective properties of cysteamine in vitro in our primary neuron and iPSC models of HD. Results:Cysteamine showed a strong neuroprotective effect (EC50 = 7.1 nM) against mutant Htt-(aa-1-586 82Q) toxicity, in a nuclear condensation cell toxicity assay. Cysteamine also rescued mitochondrial changes induced by mutant Htt. Modulation of the levels of cysteine or glutathione failed to protect neurons, suggesting that cysteamine neuroprotection is not mediated through cysteine metabolism. Taurine and Hypotaurine, which are metabolites of cysteamine can protect neurons against Htt toxicity, but the inhibition of the enzyme converting cysteamine to hypotaurine does not block either protective activity, suggesting independent protective pathways. Cysteamine has been suggested to activate BDNF secretion; however, cysteamine protection was not blocked by BDNF pathway antagonists. Conclusions:Cysteamine was strongly neuroprotective with relatively high potency. We demonstrated that the main neuroprotective pathways that have been proposed to be the mechanism of protection by cysteamine can all be blocked and still not prevent the neuroprotective effect. The results suggest the involvement of other yet-to-be-determined neuroprotective pathways.

Keywords: Huntington’s disease, huntingtin toxicity, primary neurons, neurodegeneration, neuroprotection, cysteamine, patient-derived induced pluripotent stem cells

DOI: 10.3233/JHD-180312

Journal: Journal of Huntington's Disease, vol. 8, no. 2, pp. 129-143, 2019