TY - JOUR
T1 - Cysteamine Protects Neurons from Mutant Huntingtin Toxicity
AU - Arbez, Nicolas
AU - Roby, Elaine
AU - Akimov, Sergey
AU - Eddings, Chelsy
AU - Ren, Mark
AU - Wang, Xiaofang
AU - Ross, Christopher A.
N1 - Publisher Copyright:
© 2019-IOS Press and the authors. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Cysteamine
KW - Huntingtin toxicity
KW - Huntington's disease
KW - Neurodegeneration
KW - Neuroprotection
KW - Patient-derived induced pluripotent stem cells
KW - Primary neurons
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U2 - 10.3233/JHD-180312
DO - 10.3233/JHD-180312
M3 - Article
C2 - 30856117
AN - SCOPUS:85065178893
SN - 1879-6397
VL - 8
SP - 129
EP - 143
JO - Journal of Huntington's Disease
JF - Journal of Huntington's Disease
IS - 2
ER -