N-terminal Region Of Huntingtin Research Articles

Treatment with the Glycosphingolipid Modulator THI Rescues Myelin Integrity in the Striatum of R6/2 HD Mice

Huntington's disease is one of the most common dominantly inherited neurodegenerative disorders caused by an expansion of a polyglutamine (polyQ) stretch in the N-terminal region of huntingtin (Htt). Among all the molecular mechanisms, affected by the mutation, emerging evidence proposes glycosphingolipid dysfunction as one of the major determinants. High levels of sphingolipids have been found to localize in the myelin sheaths of oligodendrocytes, where they play an important role in myelination stability and functions. In this study, we investigated any potential existing link between sphingolipid modulation and myelin structure by performing both ultrastructural and biochemical analyses. Our findings demonstrated that the treatment with the glycosphingolipid modulator THI preserved myelin thickness and the overall structure and reduced both area and diameter of pathologically giant axons in the striatum of HD mice. These ultrastructural findings were associated with restoration of different myelin marker protein, such as myelin-associated glycoprotein (MAG), myelin basic protein (MBP) and 2', 3' Cyclic Nucleotide 3'-Phosphodiesterase (CNP). Interestingly, the compound modulated the expression of glycosphingolipid biosynthetic enzymes and increased levels of GM1, whose elevation has been extensively reported to be associated with reduced toxicity of mutant Htt in different HD pre-clinical models. Our study further supports the evidence that the metabolism of glycosphingolipids may represent an effective therapeutic target for the disease.

Neuroinflammation in Huntington's disease: From animal models to clinical therapeutics.

Huntington's disease (HD) is a progressive neurodegenerative disease characterized by preferential loss of neurons in the striatum in patients, which leads to motor and cognitive impairments and death that often occurs 10-15 years after the onset of symptoms. The expansion of a glutamine repeat (>36 glutamines) in the N-terminal region of huntingtin (HTT) has been defined as the cause of HD, but the mechanism underlying neuronal death remains unclear. Multiple mechanisms, including inflammation, may jointly contribute to HD pathogenesis. Altered inflammation response is evident even before the onset of classical symptoms of HD. In this review, we summarize the current evidence on immune and inflammatory changes, from HD animal models to clinical phenomenon of patients with HD. The understanding of the impact of inflammation on HD would help develop novel strategies to treat HD.

Flanking Regions Determine the Structure of the Poly-Glutamine in Huntingtin through Mechanisms Common among Glutamine-Rich Human Proteins

The causative agent of Huntington's disease, the poly-Q homo-repeat in the N-terminal region of huntingtin (httex1), is flanked by a 17-residue-long fragment (N17) and a proline-rich region (PRR), which promote and inhibit the aggregation propensity of the protein, respectively, by poorly understood mechanisms. Based on experimental data obtained from site-specifically labeled NMR samples, we derived an ensemble model of httex1 that identified both flanking regions as opposing poly-Q secondary structure promoters. While N17 triggers helicity through a promiscuous hydrogen bond network involving the side chains of the first glutamines in the poly-Q tract, the PRR promotes extended conformations in neighboring glutamines. Furthermore, a bioinformatics analysis of the human proteome showed that these structural traits are present in many human glutamine-rich proteins and that they are more prevalent in proteins with longer poly-Q tracts. Taken together, these observations provide the structural bases to understand previous biophysical and functional data on httex1.

Modeling the Effects of Ligand Binding on the Phase Behavior of Aggregation-Prone Proteins

Many diseases are associated with aberrant protein aggregation. Recently, there has been resurgent interest in co-opting the framework of phase transitions to understand the distinct concentration thresholds separating different phases of aggregation-prone molecules. This analogy, which was purely conceptual, has now been shown to have quantitative significance. Importantly, instead of searching for elusive “toxic conformations”, dealing with the deleterious consequences of protein aggregation and phase separation can be approached via methods that alter or modulate the sequence-specific phase behavior. One route to accomplishing this is by shifting phase boundaries via ligand binding through a phenomenon known as polyphasic linkage. Disease-causing mutations, such as polyglutamine expansions in the N-terminal region of huntingtin, lead to aggregation and phase separation at lower, physiologically relevant concentration thresholds. Ligand binding can shift these phase boundaries based on the phase that is preferentially bound. Here, we show that a ligand can reduce the driving force for protein aggregation in vitro and may help to explain the reduced cellular aggregation and toxicity observed when overexpressed in the context of Huntington's disease. Through a combined biophysical and computational approach, we further show that multi-valency in binding appears to be important for shifting phase boundaries in therapeutically relevant directions. However, in the context of the cell, a protein such as huntingtin has a large interactome. Each of the interaction partners will have a different effect on the intrinsic phase boundaries and therefore, designing a therapeutic approach that leverages the tenets of polyphasic linkage requires a general framework that considers the competing effects within a network of interactions. Using the huntingtin example, we develop a framework for designing modulators of phase behavior via polyphasic linkage that accounts for competing interactions within an interactome.

Oligomerization of Huntingtin N-Terminal Fragment on a Phospholipid Bilayer Revealed by Molecular Dynamics Simulations

The Huntingtin protein is characterized by a consecutive segment of glutamines that leads, when the number of repeats exceeds a certain length, to fibrillation. Misfolding of this amyloid protein is related to the Huntington's disease through pathways that could involve interactions with phospholipid membranes. For instance, the N-terminal region of Huntingtin (httNT) positioned just before the polyglutamine segment (QN) modulates its localization to the membrane-containing organelles of the cell and can, similarly to what is observed in other amyloid proteins, perturb the physical integrity of phospholipid bilayers. To date, however, the dynamics and equilibrium structures of httNT oligomers on membranes as well as the influence of the QN region on these remain poorly understood.With the help of all-atom explicit solvent molecular dynamics simulations, we observe that the httNTQN monomer insertion in phospholipid bilayers occurs through four main steps and significantly increases the stability of the alpha-helix conformation compared to in solution. We also observe that the QN region provides, through electrostatic interactions with the phospholipids' head group, a stable scaffold to ease the insertion of httNT's non-polar residues. While the httNT monomer conformation suggested from our simulations is in agreement with a recent NMR model, its orientation in the bilayer deviates by a few degrees, a difference that might be due to the formation of dimers during the experiment. Indeed, our simulations on the dynamics of httNT dimerization, which occurs through electrostatic interactions, suggest that it affects the peptides' orientation depending on the dimer topology. Overall, these results reveal key features, at the atomic level, of httNTQN monomer and dimer interactions with phospholipid bilayer complementing previous experimental observations.

The unresolved puzzle why alanine extensions cause disease

The prospective increase in life expectancy will be accompanied by a rise in the number of elderly people who suffer from ill health caused by old age. Many diseases caused by aging are protein misfolding diseases. The molecular mechanisms underlying these disorders receive constant scientific interest. In addition to old age, mutations also cause congenital protein misfolding disorders. Chorea Huntington, one of the most well-known examples, is caused by triplet extensions that can lead to more than 100 glutamines in the N-terminal region of huntingtin, accompanied by huntingtin aggregation. So far, nine disease-associated triplet extensions have also been described for alanine codons. The extensions lead primarily to skeletal malformations. Eight of these proteins represent transcription factors, while the nuclear poly-adenylate binding protein 1, PABPN1, is an RNA binding protein. Additional alanines in PABPN1 lead to the disease oculopharyngeal muscular dystrophy (OPMD). The alanine extension affects the N-terminal domain of the protein, which has been shown to lack tertiary contacts. Biochemical analyses of the N-terminal domain revealed an alanine-dependent fibril formation. However, fibril formation of full-length protein did not recapitulate the findings of the N-terminal domain. Fibril formation of intact PABPN1 was independent of the alanine segment, and the fibrils displayed biochemical properties that were completely different from those of the N-terminal domain. Although intranuclear inclusions have been shown to represent the histochemical hallmark of OPMD, their role in pathogenesis is currently unclear. Several cell culture and animal models have been generated to study the molecular processes involved in OPMD. These studies revealed a number of promising future therapeutic strategies that could one day improve the quality of life for the patients.

F12 Abnormal regulation of macrophage-derived transforming growth factor: β 1 (TGF-β1) production in Huntington disease

<h3>Background</h3> Huntington9s Disease (HD) is a neurodegenerative disorder caused by a trinucleotide repeat (CAG) expansion within Huntingtin gene (HTT) that results in a polyglutamine (polyQ) stretch in N-terminal region of huntingtin (Htt). Mutant Htt (mHtt) interfers with several molecular pathways, including cell signalling, transcriptional regulation, axonal transport and neurotrophins production and release. Emerging evidence indicates that reduced levels of neurotrophic factors, including brain derived neurotrophic factor and transforming growth factor-β 1 (TGF-β1) are linked to the pathogenesis of HD. Previous study from our lab and collaborators, demonstrated that TGF-β1 levels varied throughout disease course in both central and peripheral tissues with a significant reduction at early stage of the disease. <h3>Aim</h3> Our aim was to clarify the contribution of each whole blood cell subset at producing TGF-β1 in the periphery and to determine whether TGF-β1 may have potential utility as a marker of disease progression. <h3>Methods</h3> Monocytes-derived macrophages from 81 HD individuals and age-matched healthy controls (n=30) were analysed by flow cytometry for the determination of TGF-β1 production. Immunohistochemical analyses were carried out for the examination of TGF-β1 expression in HD post mortem brain tissues. <h3>Results</h3> Our results indicated that the frequency of TGF-β1 expressing macrophages was significantly reduced in presymptomatic and I stage HD subjects compared to controls and increased with disease progression. Similar results were observed in HD brain tissues. <h3>Conclusion</h3> Here we demonstrated that macrophages showed variable TGF-β1 production profile during disease progression. These data correlated well with TGF-β1 immunoreactivity in HD brain tissues. Collectively we described an interesting link between production of TGF-β1 in the periphery and central defect and highlighted the potential of TGF-β1 as a possible novel marker for disease progression.

B04 AMPK activation alleviates phenotypes associated to the early phases of mutant polyQ cytoxicity

<h3>Background</h3> Huntington9s disease (HD) is a neurodegenerative disorder induced by cell toxicity caused by polyglutamine (polyQ) expansion in the N-terminal region of huntingtin (Htt). We use <i>C elegans</i> expressing 128Q in neurons to screen for genes that modulate the early phases (neuron dysfunction) of mutant polyQ cytotoxicity. Using these worms we have shown previously the neuroprotective roles of sirtuin <i>sir-2.1</i>/SIRT1 and <i>daf-16</i>/FoxO. Here, we report that AMPK, an energy sensor involved health span extension in worms and mammals, has neuroprotective effects against the early phases of mutant polyQ cytotocity. <h3>Aims</h3> Here we characterise AMPK in the context of neuronal dysfunction/cell vunerability caused by mutant forms of htt in models of HD. <h3>Methods</h3> We studied the function of AMPK in <i>C elegans</i>, and its potential interaction with neuroprotective genes (ie, <i>daf-16</i>/FOXO and <i>sir-2.1</i>/Sirtuin), by using mutants combined with transgenesis and drugs. We then confirmed the protective role of mammalian AMPK in striatal cells derived from htt knock-in mice. Finally we tested for the effect of AMPK activation in mice that express mutant htt. <h3>Results</h3> By using genetic analysis in worms, we show that AMPK is required for protection against neuron dysfunction through the <i>daf-16</i>/FOXO-<i>sir-2.1</i>/Sirtuin signalling network. We show that depletion of AMPK enhances neuronal impairment, and that activation by metformin induces neuroprotection, suggesting that this enzyme may be of therapeutic interest to fight the early phases of HD. We tested depletion and activation of this enzyme, in striatal cells from knock-in mice, a cell vulnerability model. Reducing AMPK, by siRNA, enhanced the susceptibility to cell death in mutant htt cells, and AMPK activation promotes striatal cell survival. Interestingly, activation of AMPK in striatal cells reduces the level of soluble mutant htt, suggesting that AMPK activation may promote protein clearance in these cells. Finally, we show that expression of gain-of-function form of AMPK in mice, expressing N-terminal expanded htt, reduce the volume of the lesion caused by neurodegeneration in the striatum. <h3>Conclusion</h3> These results strongly suggest that AMPK activation protects from the early phases of mutant htt cytoxicity in several models of HD.

Influence of Species Differences on the Neuropathology of Transgenic Huntington's Disease Animal Models

Transgenic animal models have revealed much about the pathogenesis of age-dependent neurodegenerative diseases and proved to be a useful tool for uncovering therapeutic targets. Huntington's disease is a well-characterized neurodegenerative disorder that is caused by expansion of a CAG repeat, which results in expansion of a polyglutamine tract in the N-terminal region of huntingtin (HTT). Similar CAG/glutamine expansions are also found to cause eight other neurodegenerative diseases that affect distinct brain regions in an age-dependent manner. Identification of this CAG/glutamine expansion has led to the generation of a variety of transgenic animal models. Of these different animal models, transgenic mice have been investigated extensively, and they show similar neuropathology and phenotypes as seen in their respective diseases. The common pathological hallmark of age-dependent neurodegeneration is the formation of aggregates or inclusions consisting of misfolded proteins in the affected brain regions; however, overt or striking neurodegeneration and apoptosis have not been reported in most transgenic mouse models for age-dependent diseases, including HD. By comparing the neuropathology of transgenic HD mouse, pig, and monkey models, we found that mutant HTT is more toxic to larger animals than mice, and larger animals also show neuropathology that has not been uncovered by transgenic mouse models. This review will discuss the importance of transgenic large animal models for analyzing the pathogenesis of neurodegenerative diseases and developing effective treatments.

A huntingtin–HAP1–PCM1 pathway in ciliogenesis

Evaluation of: Keryer G, Pineda JR, Liot G et al. Ciliogenesis is regulated by a huntingtin–HAP1–PCM1 pathway and is altered in Huntington disease. J. Clin. Invest. 121(11), 4372–4382 (2011).Huntington’s disease (HD) is caused by expansion of a polyglutamine repeat in the N-terminal region of huntingtin (htt), a large protein that has been found to interact with a variety of proteins. It remains to be determined how the interactions of htt with other proteins are involved in the pathogenesis of HD. A recent publication by Keryer et al. demonstrates that htt regulates ciliogenesis by interacting with PCM1 through HAP1. This recent study shows that htt and HAP1 are essential for protein trafficking to the centrosome, as well as normal ciliogenesis, and that mutant htt causes abnormal ciliogenesis, providing a novel insight into the pathogenesis of HD.

Preferential accumulation of N-terminal mutant huntingtin in the nuclei of striatal neurons is regulated by phosphorylation

An expanded polyglutamine tract (>37 glutamines) in the N-terminal region of huntingtin (htt) causes htt to accumulate in the nucleus, leading to transcriptional dysregulation in Huntington disease (HD). In HD knock-in mice that express full-length mutant htt at the endogenous level, mutant htt preferentially accumulates in the nuclei of striatal neurons, which are affected most profoundly in HD. The mechanism underlying this preferential nuclear accumulation of mutant htt in striatal neurons remains unknown. Here, we report that serine 16 (S16) in htt is important for the generation of small N-terminal fragments that are able to accumulate in the nucleus and form aggregates. Phosphorylation of N-terminal S16 in htt promotes the nuclear accumulation of small N-terminal fragments and reduces the interaction of N-terminal htt with the nuclear pore complex protein Tpr. Mouse brain striatal tissues show increased S16 phosphorylation and a decreased association between mutant N-terminal htt and Tpr. These findings provide mechanistic insight into the nuclear accumulation of mutant htt and the selective neuropathology of HD, revealing potential therapeutic targets for treating this disease.

Lack of interleukin-1 type 1 receptor enhances the accumulation of mutant huntingtin in the striatum and exacerbates the neurological phenotypes of Huntington's disease mice

Huntington's disease results from expansion of a glutamine repeat (>36 glutamines) in the N-terminal region of huntingtin (htt) and is characterized by preferential neurodegeneration in the striatum of the brain. N171-82Q mice that express N-terminal 171 amino acids of htt with an 82-glutamine repeat show severe neurological phenotypes and die early, suggesting that N-terminal mutant htt is pathogenic. In addition, various cellular factors and genetic modifiers are found to modulate the cytotoxicity of mutant htt. Understanding the contribution of these factors to HD pathogenesis will help identify therapeutics for this disease. To investigate the role of interleukin type 1 (IL-1), a cytokine that has been implicated in various neurological diseases, in HD neurological symptoms, we crossed N171-82Q mice to type I IL-1 receptor (IL-1RI) knockout mice. Mice lacking IL-1RI and expressing N171-82Q show more severe neurological symptoms than N171-82Q or IL-1RI knockout mice, suggesting that lack of IL-1RI can promote the neuronal toxicity of mutant htt. Lack of IL-1RI also increases the accumulation of transgenic mutant htt in the striatum in N171-82Q mice. Since IL-1RI signaling mediates both toxic and protective effects on neurons, its basal function and protective effects may be important for preventing the neuropathology seen in HD.

Inhibiting the ubiquitin–proteasome system leads to preferential accumulation of toxic N-terminal mutant huntingtin fragments

An expanded polyglutamine (polyQ) domain in the N-terminal region of huntingtin (htt) causes misfolding and accumulation of htt in neuronal cells and the subsequent neurodegeneration of Huntington's disease (HD). Clearing the misfolded htt is critical for preventing neuropathology, and this process is mediated primarily by both the ubiquitin-proteasome system (UPS) and autophagy. Although overexpression of mutant htt can inhibit UPS activity in cultured cells, mutant htt does not inhibit global UPS activity in the brains of HD transgenic mice. These findings underscore the importance of investigating the function of the UPS and autophagy in the brain when mutant proteins are not overexpressed. When cultured PC12 cells were treated with either UPS or autophagy inhibitors, more N-terminal mutant htt fragments accumulated via inhibition of the UPS. Furthermore, in HD CAG repeat knock-in mouse brain, inhibiting the UPS also resulted in a greater accumulation of N-terminal, but not full-length, mutant htt than inhibiting autophagy did. Our findings suggest that impairment of the UPS may be more important for the accumulation of N-terminal mutant htt and might therefore make an attractive therapeutic target.

Monoclonal Antibodies Recognize Distinct Conformational Epitopes Formed by Polyglutamine in a Mutant Huntingtin Fragment

Huntington disease (HD) is a neurodegenerative disorder caused by an expansion of a polyglutamine (polyQ) domain in the N-terminal region of huntingtin (htt). PolyQ expansion above 35-40 results in disease associated with htt aggregation into inclusion bodies. It has been hypothesized that expanded polyQ domains adopt multiple potentially toxic conformations that belong to different aggregation pathways. Here, we used atomic force microscopy to analyze the effect of a panel of anti-htt antibodies (MW1-MW5, MW7, MW8, and 3B5H10) on aggregate formation and the stability of a mutant htt-exon1 fragment. Two antibodies, MW7 (polyproline-specific) and 3B5H10 (polyQ-specific), completely inhibited fibril formation and disaggregated preformed fibrils, whereas other polyQ-specific antibodies had widely varying effects on aggregation. These results suggest that expanded polyQ domains adopt multiple conformations in solution that can be readily distinguished by monoclonal antibodies, which has important implications for understanding the structural basis for polyQ toxicity and the development of intrabody-based therapeutics for HD.

Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice

Huntington's disease (HD) is caused by the expansion of a polyglutamine tract in the N-terminal region of huntingtin (htt) and is characterized by selective neurodegeneration. In addition to forming nuclear aggregates, mutant htt accumulates in neuronal processes as well as synapses and affects synaptic function. However, the mechanism for the synaptic toxicity of mutant htt remains to be investigated. We targeted fluorescent reporters for the ubiquitin–proteasome system (UPS) to presynaptic or postsynaptic terminals of neurons. Using these reporters and biochemical assays of isolated synaptosomes, we found that mutant htt decreases synaptic UPS activity in cultured neurons and in HD mouse brains that express N-terminal or full-length mutant htt. Given that the UPS is a key regulator of synaptic plasticity and function, our findings offer insight into the selective neuronal dysfunction seen in HD and also establish a method to measure synaptic UPS activity in other neurological disease models.

Context-dependent Dysregulation of Transcription by Mutant Huntingtin

Huntington disease (HD) is an adult-onset neurodegenerative disease caused by expansion of a polyglutamine (poly(Q) tract in the N-terminal region of huntingtin (htt). Although the precise mechanisms leading to neurodegeneration in HD have not been fully elucidated, transcriptional dysregulation has been implicated in disease pathogenesis. In HD, multiple N-terminal mutant htt fragments smaller than the first 500 amino acids have been found to accumulate in the nucleus and adversely affect gene transcription. It is unknown whether different htt fragments in the nucleus can differentially bind transcription factors and affect transcription. Here, we report that shorter N-terminal htt fragments, which are more prone to misfolding and aggregation, are more competent to bind Sp1 and inhibit its activity. These effects can be reversed by Hsp40, a molecular chaperone that reduces the misfolding of mutant htt. Our results provide insight into the beneficial effects of molecular chaperones and suggest that context dependent transcriptional dysregulation may contribute to differential toxicity of various N-terminal htt fragments.

Epitope Mapping of Monoclonal Antibody 4C8 Recognizing the Protein Huntingtin

Huntington's disease is a dominantly inherited, devastating neurodegenerative disorder, caused by a polyglutamine expansion (>37) in the N-terminal region of huntingtin, a protein of unknown function. In patients and normal individuals, N-terminal fragments of huntingtin are found, and the N-terminal fragments of mutant huntingtin are cytotoxic. The functions of wild-type huntingtin and the mechanisms underlying the toxic effects of mutant huntingtin are still ill defined. To get more insight into these topics, monoclonal antibodies (MAbs) are indispensable tools. Antibodies raised against the N-terminus are especially important. Among these, the 4C8 mouse MAb has been extensively used in various approaches. In this study, we have mapped the epitope of 4C8 to a 15-amino acid (aa) region spanning from aa 443 to 457 of the human protein, and found that mutation of three consecutive glutamic acids present in this region disrupts the recognition by 4C8. These results allow a more accurate interpretation of the results obtained by usage of the 4C8 antibody and broaden the utility of this antibody.

Huntington and its Role in Neuronal Degeneration

Huntington’s disease results from a polyglutamine expansion in the N-terminal region of huntingtin (htt). This abnormality causes protein aggregation and leads to neurotoxicity. Despite its widespread expression in the brain and body, mutant htt causes selective neurodegeneration in Huntington’s disease patient brains. However, Huntington’s disease mouse models expressing mutant htt do not have obvious neurodegeneration despite significant neurological symptoms. Most Huntington’s disease mouse models display the accumulation of toxic N-terminal mutant htt fragments in both the nucleus and neuronal processes, suggesting that these subcellular sites are hotspots for the early neuropathology of Huntington’s disease. Intranuclear htt affects gene expression and may cause neuronal dysfunction. Mutant htt in neuronal processes affects axonal transport and induces degeneration, and these effects may be more relevant to the selective neurodegeneration in Huntington’s disease. Growing evidence has also suggested that mutant htt mediates multiple pathological pathways. This review discusses the early pathological changes identified in Huntington’s disease cellular and animal models. These changes may be the causes of neurode-generation.

Huntingtin is degraded to small fragments by calpain after ischemic injury☆

The gene defect in Huntington’s disease (HD) causes a polyglutamine expansion in the N-terminal region of huntingtin (N-htt). In vitro studies suggest that mutant N-htt fragments can aggregate and cause cell death in HD. The physiological and pathological conditions that affect htt proteolysis in the brain are unclear. We examined htt expression by Western blot in the rat brain after transient ischemic injury, which causes striatal neurodegeneration similar to that seen in HD and activates proteases including calcium-dependent calpains. Focal brain ischemia reduced levels of full-length htt in the infarcted cortex and striatum and increased expression of a 55-kDa N-htt fragment that was also produced by treating control brain extracts with calpain. N-htt fragments between 65 and 80 kDa also rose after injury, but these fragments were not as long-lived as the 55-kDa N-htt fragment. The results suggest that after ischemic injury full-length htt is degraded in degenerating neurons and an N-htt fragment accumulates.

In vitro expression systems for the Huntington protein.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder resulting from expansion (>37 units) of a polyglutamine tract in huntingtin, a 350 kDa protein of unknown function (). The N-terminal region of huntingtin contains the glutamine repeat, which is encoded by exon1 of the HD gene. Normal huntingtin is a cytoplasmic protein and is expressed ubiquitously, but N-terminal fragments of huntingtin with expanded polyglutamine tracts are able to accumulate in the nucleus and form aggregates. A large body of evidence has shown that N-terminal huntingtin with expanded glutamine repeats is toxic and can kill cells (, , , , , , ). For example, transgenic mice (R6/2) expressing the HD exon1 protein with more than 115 glutamines develop neurological symptoms and neuronal intranuclear inclusions consisting of huntingtin aggregates (). Similar nuclear aggregates are found in patients with HD (, , ) and other polyglutamine diseases ().