Quantitative Relationships between Huntingtin Levels, Polyglutamine Length, Inclusion Body Formation, and Neuronal Death Provide Novel Insight into Huntington's Disease Molecular Pathogenesis

Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2010; 30(31):10541-50. DOI: 10.1523/JNEUROSCI.0146-10.2010
Source: PubMed


An expanded polyglutamine (polyQ) stretch in the protein huntingtin (htt) induces self-aggregation into inclusion bodies (IBs) and causes Huntington's disease (HD). Defining precise relationships between early observable variables and neuronal death at the molecular and cellular levels should improve our understanding of HD pathogenesis. Here, we used an automated microscope that tracks thousands of neurons individually over their entire lifetime to quantify interconnected relationships between early variables, such as htt levels, polyQ length, and IB formation, and neuronal death in a primary striatal model of HD. The resulting model revealed that mutant htt increases the risk of death by tonically interfering with homeostatic coping mechanisms rather than producing accumulated damage to the neuron, htt toxicity is saturable, the rate-limiting steps for inclusion body formation and death can be traced to different conformational changes in monomeric htt, and IB formation reduces the impact of the starting levels of htt of a neuron on its risk of death. Finally, the model that emerges from our quantitative measurements places critical limits on the potential mechanisms by which mutant htt might induce neurodegeneration, which should help direct future research.

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Available from: Jason Matthew-Lewis Miller, Aug 25, 2015
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    • "Although this study demonstrated that IB formation is reversible, it did not address whether IBs are cleared all at once or dissolved gradually. Later work showed that IBs in mHtt-expressing neurons disappear abruptly (Arrasate et al., 2004; Miller et al., 2010), suggesting that neurons can spontaneously and rapidly metabolize IBs. Autophagy and the ubiquitin-proteasome system (UPS) have been implicated in this metabolism. "
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    ABSTRACT: Selective neuronal loss is a hallmark of neurodegenerative diseases, including Huntington's disease (HD). Although mutant huntingtin, the protein responsible for HD, is expressed ubiquitously, a subpopulation of neurons in the striatum is the first to succumb. In this review, we examine evidence that protein quality control pathways, including the ubiquitin proteasome system, autophagy, and chaperones, are significantly altered in striatal neurons. These alterations may increase the susceptibility of striatal neurons to mutant huntingtin-mediated toxicity. This novel view of HD pathogenesis has profound therapeutic implications: protein homeostasis pathways in the striatum may be valuable targets for treating HD and other misfolded protein disorders.
    Full-text · Article · Aug 2014 · Frontiers in Cellular Neuroscience
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    • "It is generally known that HD is a neurodegenerative movement disorder caused by genetic mutation and morphologically characterized by progressive but selective loss of neurons, primarily within the striatum, followed by the development of reactive gliosis (e.g., [52]). Regardless of some in vitro studies which indicated formation of polyQ inclusions that reduce levels of mhtt and the risk of neuronal death [10, 11], it was suggested that the aberrant protein huntingtin (mhtt) with an expansion of N-terminal polyglutamine tract causes preferentially degeneration of striatal neurons in patients with HD (e.g., [6]). Moreover, a gain of a new toxic function of the mhtt results in the loss of former protective functions of wild-type htt, which ultimately leads to the death of neurons [8]. "
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    ABSTRACT: Rats transgenic for Huntington’s disease (tgHD51 CAG rats), surviving up to two years, represent an animal model of HD similar to the late-onset form of human disease. This enables us to follow histopathological changes in course of neurodegenerative process (NDP) within the striatum and compare them with postmortem samples of human HD brains. A basic difference between HD pathology in human and tgHD51 rats is in the rate of NDP progression that originates primarily from slow neuronal degeneration consequently resulting in lesser extent of concomitant reactive gliosis in the brain of tgHD51 rats. Although larger amount of striatal neurons displays only gradual decrease in their size, their number is significantly reduced in the oldest tgHD51 rats. Our quantitative analysis proved that the end of the first year represents the turn in the development of morphological changes related to the progression of NDP in tgHD51 rats. Our data also support the view that all types of CNS glial cells play an important, irreplaceable role in NDP. To the best of our knowledge, our findings are the first to document that tgHD51 CAG rats can be used as a valid animal model for detailed histopathological studies related to HD in human.
    Full-text · Article · Aug 2014 · BioMed Research International
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    • "E. coli has been employed to follow in vivo the aggregation process of an artificial protein harboring a polyglutamine (polyQ) tract (Ignatova et al., 2007). E. coli growth rate was found to be sensitive to the protein conformational state, and showed that misfolded peptides and soluble aggregates were cytotoxic (Miller et al., 2010). "
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    ABSTRACT: The formation of inclusion bodies (IBs) constitute a frequent event during the production of heterologous proteins in bacterial hosts. Although the mechanisms leading to their formation are not completely understood, empirical data have been exploited trying to predict the aggregation propensity of specific proteins while a great number of strategies have been developed to avoid the generation of IBs. However, in many cases, the formation of such aggregates can be considered an advantage for basic research as for protein production. In this review, we focus on this positive side of IBs formation in bacteria. We present a compilation on recent advances on the understanding of IBs formation and their utilization as a model to understand protein aggregation and to explore strategies to control this process. We include recent information about their composition and structure, their use as an attractive approach to produce low cost proteins and other promising applications in Biomedicine.
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