Abstract
Huntington's disease (HD) is an untreatable neurological disorder caused by selective and progressive degeneration of the caudate nucleus and putamen of the basal ganglia. Although the etiology of HD pathology is not fully understood, the observed loss of neuronal cells is thought to occur primarily through apoptosis. Furthermore, there is evidence in HD that cell death is mediated through mitochondrial pathways, and mitochondrial deficits are commonly associated with HD. We have previously reported that treatment with tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, prevented neuropathology and associated behavioral deficits in the 3-nitropropionic acid rat model of HD. We therefore examined whether TUDCA would also be neuroprotective in a genetic mouse model of HD. Our results showed that systemically administered TUDCA led to a significant reduction in striatal neuropathology of the R6/2 transgenic HD mouse. Specifically, R6/2 mice began receiving TUDCA at 6 weeks of age and exhibited reduced striatal atrophy, decreased striatal apoptosis, as well as fewer and smaller size ubiquitinated neuronal intranuclear huntingtin inclusions. Moreover, locomotor and sensorimotor deficits were significantly improved in the TUDCA-treated mice. In conclusion, TUDCA is a nontoxic, endogenously produced hydrophilic bile acid that is neuroprotective in a transgenic mouse model of HD and, therefore, may provide a novel and effective treatment in patients with HD.
Highlights
Huntington’s disease (HD) is a heritable disorder caused by abnormal expansion of the trinucleotide (CAG) repeat sequence in exon 1 of the gene (Htt) encoding the huntingtin protein [1]
Tauroursodeoxycholic acid (TUDCA)-treated 11-week-old animals showed improved Rota-Rod performance at 25 rpm (TU, 104 Ϯ 24 sec; Tg, 47 Ϯ 7 sec; P Ͻ 0.05) and at 15 rpm (TU, 222 Ϯ 36 sec; Tg, 139 Ϯ 31 sec; P Ͻ 0.05), and 12-week-old animals were better at 5 rpm (TU, 395 Ϯ 50 sec; Tg, 279 Ϯ 44 sec; P Ͻ 0.05). These results suggest that TUDCA improves sensorimotor deficits in HD mice, and age and task difficulty influence the observed degree of behavioral recovery
TUDCA is a unique bile acid that acts as a potent anti-apoptotic agent
Summary
Huntington’s disease (HD) is a heritable disorder caused by abnormal expansion of the trinucleotide (CAG) repeat sequence in exon 1 of the gene (Htt) encoding the huntingtin protein [1] This expansion results in the selective death of neurons in the caudate and putamen, with secondary pre- and postsynaptic cell loss. TUDCA mitigates mitochondrial insufficiency and toxicity, and prevents apoptosis, in part, by inhibiting Bax translocation from cytosol to the mitochondria. In hepatocytes, this inhibition results in reduced mitochondrial membrane perturbation, release of cytochrome c, and activation of downstream caspases [24, 27,28,29,30]. Intracellular inclusions were significantly reduced, and the TUDCA-treated mice showed improved locomotor and sensorimotor abilities
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