Huntington disease and the huntingtin protein.

Hope Center for Neurological Diseases, Knight-Alzheimer Disease Research Center, Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
Progress in molecular biology and translational science (Impact Factor: 3.11). 01/2012; 107:189-214. DOI: 10.1016/B978-0-12-385883-2.00010-2
Source: PubMed

ABSTRACT Huntington disease (HD) is a devastating neurodegenerative disease that derives from CAG repeat expansion in the huntingtin gene. The clinical syndrome consists of progressive personality changes, movement disorder, and dementia and can develop in children and adults. The huntingtin protein is required for human development and normal brain function. It is subject to posttranslational modification, and some events, such as phosphorylation, can play an enormous role in regulating toxicity of the huntingtin protein. The function of huntingtin in the cell is unknown, and it may play a role as a scaffold. Multiple mouse models of HD have now been created with fragments and full-length protein. The models show variable fidelity to the disease in terms of genetics, pathology, and rates of progression. Pathogenesis of HD involves cleavage of the protein and is associated with neuronal accumulation of aggregated forms. The potential mechanisms of neurodegeneration are myriad, including primary effects of protein homeostasis, gene expression, and mitochondrial dysfunction. Specific therapeutic approaches are similarly varied and include efforts to reduce huntingtin gene expression, protein accumulation, and protein aggregation.

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    ABSTRACT: Huntington's disease is a hereditary movement disorder that is characterized by progressive neuronal cell death mainly in the cortex and striatum of the brain. It is caused by an unstable CAG repeat extension in the first exon of the IT-15 gene which encodes a protein called huntingtin (Htt). The trinucleotide expansion translates into an elongated polyglutamine (polyQ) stretch. A polyQ length of more than 35 glutamine residues is associated with the appearance of huntingtin aggregates and the development of the disease. The process of aggregation is not fully understood but its inhibition and its modulation provide an insight into the mechanisms leading to aggregate formation which might be a target for the treatment of the disease. Using CFP-and YFP-tagged huntingtin exon 1 fragments we established a cellular model that visualizes the process of huntingtin aggregation and in which the aggregates could be specifically detected by FRET microscopy (acceptor photobleaching and fluorescence lifetime microscopy). The time course of the aggregation process was investigated by image analysis. 1. Role of huntingtin aggregates in Huntington's disease Huntington's disease (HD) (OMIM 143100) is a autosomal dominant, age-at-onset, progressive neurodegenerative disorder caused by an expanded (CAG)n repeat in the exon 1 of the huntingtin gene IT-15 located on chromosome 4 [1]. The expansion above the normal range of 6–35 CAG repeats leads to an elongated poly-glutamine (polyQ) tract that causes misfolding and aberrant protein-protein interactions thereby conferring a multifaceted toxic gain of function to the widely expressed huntingtin protein. The age of onset is most critically determined by and inversely correlated with the length of the expanded CAG repeat. HD is characterized by neurodegeneration and formation of neuronal intranuclear and cytoplasmic accumulation of aggregated mutant huntingtin, particularly in the striatum and cortex but also extended to other brain regions. The resulting clinical phenotype summarizes progressive movement dysfunction, cognitive impairments, psychiatric symptoms, and ultimately death. Currently, no cure or therapy for delaying HD-associated symptoms is available. HD belongs to a set of ten, dominantly inherited neurodegenerative disorders, the polyglutamine (polyQ) diseases, each caused by expanded polyglutamine (polyQ) tracts in otherwise unrelated proteins [2, 3]. HD pathophysiological processes are multiple, complex and variable including impairments of transcription, axonal transport, ubiquitin proteasome system and of mitochondrial function. A key feature in HD pathogenesis is the poly(Q) dependent self-association and aggregation of mutant huntingtin proteins and of N-terminal toxic htt peptides generated by proteolytic cleavage. Thereby, aggregates in the nucleus (nuclear inclusions) but also in the cytoplasm, e.g. neuropils, are formed [4, 5]. The mutant huntingtin can undergo different conformations including aberrantly folded monomeric forms, a wide-range of oligomeric species, fibril states, and larger insoluble aggregates [6]. The role of mutant huntingtin aggregation in the pathogenesis of HD as well as the toxic impact of different forms of mutant Htt is intensely discussed. Aggregation-mediated sequestration of proteins with essential cellular functions could be harmful to the cell, whereas a protective mechanism resulting from sequestration of the toxic Htt moiety or other cellular proteins which stimulate mutant Htt clearance would be beneficial. Furthermore, different structures of mHtt aggregates seem to determine the nature of proteins being trapped. Thus, the resulting toxic effects are also driven by whichever cell-specific proteins are present. Altogether, this may account for selective dysfunction and degeneration in HD. As a consequence, the modulation of mHtt aggregation could have beneficial effects on overall toxicity or specific cellular pathways deregulated in HD. This has been successfully shown by the interaction of a specific intrabody with mutant huntingtin leading to increased ubiquitination and clearance of cytoplasmic mHtt as well as a subsequent prevention of mHtt accumulation in neuronal processes and a reduced neurotoxicity [7]. Modulation of the mHtt aggregation process by shifting the equilibrium toward soluble huntingtin was achieved by reducing the level of histone deacetylase HDAC4. The resulted delay in cytoplasmic mHtt aggregation alleviated disease progression and led to improvement of neurological phenotypes in an HD mouse model. These data clearly indicate that cytoplasmic aggregation mechanisms contribute to HD-related neurodegenerative phenotypes [8]. Elucidating the relationship of different forms of mHtt aggregates to toxicity and to disease progression is thus an important step in the pathway to therapeutic interventions. In order to study HD pathomechanisms considerable effort has been invested in the development of in vitro and in vivo model systems [6, 9]. One way to study the fate of proteins in living cells is to use fluorescent protein (FP) fusions. Proteins tagged with FPs often retain their biochemical properties and allow the functional analysis of proteins in living cells. In combination with microscopic techniques FP tags are ideally suited to analyse spatio-temporal processes such Microscopy: advances in scientific research and education (A. Méndez-Vilas, Ed.)
    Microscopy: advances in scientific research and education, Edited by Antonio Méndez-Vilas, 09/2014: chapter Analysis of huntingtin aggregation by fluorescence and FRET microscopy: pages 217-225; Formatex Research Center., ISBN: 978-84-942134-3-4