HD Lighthouse Editors Comment:Researchers call mice without HD 'wild type mice'. In the TUDCA-mice experiments the TUDCA treated HD mice did very much better than the untreated HD mice. The TUDCA mice lagged a bit in performance when compared to the wild type mice. The researchers think that the TUDCA mice may not show any defects if treatment begins closer to birth. -- Jerry

Posted to HDLighthouse: 02Aug02 HDL Update: TUDCA

TUDCA In HD patients and animal models of HD, mitochondrial insufficiency and apoptosis are significant indicators of disease progression that could potentially be reduced by TUDCA.

Discussion

TUDCA is a unique bile acid that acts as a potent anti-apoptotic agent. In addition to its antioxidant properties, it inhibits mitochondrial processes, such as mitochondrial permeability transition, cytochrome c release, Bax translocation, and caspase activation. We have shown that administration of TUDCA, a nontoxic, endogenously produced, hydrophilic bile acid, to a genetic mouse model of HD significantly reduced striatal neurodegeneration and ameliorated locomotor and sensorimotor deficits. This study extends our previous reports in pharmacologic animal models of HD and suggests that TUDCA may be a viable therapeutic option for the treatment of HD.

TUDCA treatment of the R6y2 Tg mice reduced striatal atrophy and the number of apoptotic cells and resulted in fewer pathophysiological pathways, including increased oxidative stress, mitochondrial toxicity, intracellular signaling disruption, and extracellular neurotrophic impairment (17). Aberrant mutant huntingtin interaction with its effector proteins provides a likely mechanism, as caspase activation is a consequence of abnormal interactions between mutant huntingtin and its effector proteins. It has been shown that reduced binding affinity of mutant huntingtin to Hip-1 results in the activation of Hip-1yHippiycaspase-8-mediated apoptotic cascades. Huntingtin contains intrinsic caspase cleavage sites, and polyglutamine expansions make striatal neurons more likely to generate active caspases. Also, the rate of caspase cleavage is positively correlated with CAG repeat length; truncated huntingtin is more toxic than its full length counterpart, and more readily redistributes to the nucleus and forms nuclear aggregates . Moreover, caspase cleavage resistant huntingtin exhibits lower toxicity and aggregate formation than the unaltered protein).

Caspase mediated apoptosis may not be the predominant mechanism of HD pathophysiology. In fact, there is evidence to show that HD symptomatology occurs before extensive striatal cell death, and apoptosis tends to be an acute, rather than chronic, process. In fact, in the initial characterization of the R6y2 Tg HD mouse, no significant cell death was detected. Thus, it is possible that apoptosis contributes significantly only at the later stages of the disease, as observed in this study. The slowly developing vulnerability of striatal neurons to mutant huntingtin could be caused by a direct, abnormal interaction between mutant huntingtin and the mitochondria that causes a progressive accumulation of cytotoxic molecules. It could also be caused by huntingtin aggregate mediated impairment of intracellular trafficking or signaling, with subsequent cytoplasmic and mitochondrial insult, leading to elevated cytotoxicity. In either case, as caspase activity increases and huntingtin is cleaved at higher frequencies, toxic N-terminal huntingtin fragments are generated that accelerate cytotoxicity through further activation of caspases and impairment of transcriptional activity after nuclear translocation. Thus, by reducing mutant huntingtin, stabilizing mitochondria, and preventing apoptotic pathways, TUDCA may be acting at multiple levels to protect vulnerable cells in the caudate and putamen, and may reduce HD pathology by derailing pathophysiologic mechanisms early in the process.

TUDCA treated HD mice exhibited reduced striatal neuropathology, with associated improvement of motor abilities. Improved performance in TUDCA treated animals depended on task difficulty. Younger TUDCA treated mice performed better at more difficult rotational speeds, whereas older mice were less impaired at slower velocities. This finding supports the progressive nature of the pathology in the Tg mice, and demonstrates their accuracy to the human condition. Our results also underscore the relationship between task difficulty and ability. We chose several rotational speeds based on the notion that TUDCA would improve Rota-Rod performance in Tg mice, but might not be evident at exceptionally easy or difficult tasks. Although wt mice mastered each rotational velocity, the TUDCA treated mice were not able to achieve those levels. This result may be caused by the delayed TUDCA treatment, which did not begin until the animals were 6 weeks old.

Although prominent behavioral deficits do not present before the eighth week of age (34), a significant degree of subcellular pathology occurs before mice become symptomatic. For example, in 4 to 6 week old presymptomatic R6y2 mice, expression of certain striatal signaling genes, as well as proteins important for neurotransmission, is significantly reduced. In addition, marked striatal and cortical neuron atrophy is detectable at 6 weeks of age. Thus, significant pathophysiology and neurodegeneration had occurred before TUDCA administration. Further studies are required to establish the most efficient dosing schedule and route of administration of TUDCA to significantly prolong the life span of Tg HD mice.

The present study extends results showing a neuroprotective effect of TUDCA in the 3-NP rat model of HD (32). Although the 3-NP model is a well studied and accepted animal model of the disease (59, 60), it is unknown whether the mechanism of neurotoxicity of 3-NP is representative of HD pathophysiology. HD patients exhibit signs of mitochondrial stress and insufficiency), and 3-NP toxicity is mediated by irreversible inhibition of succinate dehydrogenase, which is a key metabolic enzyme. However, Tg animal models of HD may represent more accurate models because they bridge the gap between genetic mutation and mitochondrial pathophysiology. We chose the R6y2 mouse model because it is a well characterized genetic animal model of HD, and because the severity of symptomatology and disease progression provides a basis with which to evaluate therapeutic efficacy in fulminant HD.

In HD patients and animal models of HD, mitochondrial insufficiency and apoptosis are significant indicators of disease progression that could potentially be reduced by TUDCA. Previous studies with TUDCA have focused on the antiapoptotic and cytoprotective effects in hepatic systems, and most recently in acute stroke. This study, combined with previous work in the 3-NP rat model (32), supports the continued evaluation of TUDCA for the treatment of HD. Furthermore, a multitude of neurological disorders, including Friedreich’s ataxia, amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease, are mediated in some fashion through mitochondrial perturbation). TUDCA may, therefore, exhibit neuroprotective properties in other chronic neurological conditions.

This work was supported by the Lyle French Fund and the National Institute of Mental Health.

Source: Discussion from Proc Natl Acad Sci U S A 2002 Jul 29. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease Keene CD, et al. PDF File

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