Cholesterol metabolism and homeostasis in the brain

Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to bloodbrain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms.     

Is Huntington disease a developmental disorder?

The recently discovered roles of huntingtin in non-differentiated cells indicate that it is a key molecule in brain development. Humbert argues that the haploinsufficiency of wild-type huntingtin in Huntington disease might lead to various cellular alterations well before the onset of symptoms and ultimately cause disease.The construction of an organism is a complex process that involves a developmental challenge: the orchestrated proliferation, migration and differentiation of cells, leading to the assembly of organs. Huntingtin—the protein that is mutated in the neurodegenerative disorder Huntington disease—is widely expressed in the early developing mouse embryo, in which it has an essential role. The most compelling proof that huntingtin is essential for early development is that inactivation of the murine gene results in defects in extra-embryonic tissues and embryonic death at embryonic day 7.5 (Dragatsis et al, 1998). My group has recently directly linked a cellular function of huntingtin to brain development (Godin et al, 2010a). Indeed, huntingtin regulates cortical neurogenesis through, at least in part, its role during spindle pole orientation.The growing evidence that huntingtin functions during development opens the door to viewing Huntington disease as a developmental disorder. Development could be abnormal in carriers of the mutant protein and precede the manifestation of the disease by decades. Changes during development might not have phenotypical consequences until the mature cells are required to function later in life. Indeed, a given protein will not function in the same context during development and adulthood, and the resulting phenotypes of these functions will not be the same. Furthermore, compensatory mechanisms that respond to abnormal development might be overwhelmed when the organism is ageing. We have not yet identified all of the neurodevelopmental defects—both functional and morphological—involved in Huntington disease. However, there are changes in the brain before the onset of disease, including a smaller intracranial adult brain volume in pre-manifest Huntington disease carriers (Nopoulos et al, 2010). It is tempting to consider that this might be a consequence of altered brain development.A complex molecular picture of the biology of huntingtin is emerging, suggesting that it is a scaffold protein that could couple many cellular events. Huntingtin regulates the assembly of the dynein–dynactin complex for axonal transport and Golgi apparatus organization (Caviston et al, 2007; Gauthier et al, 2004). During cell division, this role extends to a complex that also contains NuMA, a component that is essential for the organization of microtubules at the spindle pole (Godin et al, 2010a). Furthermore, NuMA and the Goloco-containing protein LGN form a complex that regulates the interaction between astral microtubules and the cell cortex (Du & Macara, 2004). Therefore, huntingtin could also participate in the distribution of the dynein–dynactin complex at the cell cortex and, as a consequence, regulate mitosis at several points. Similarly, huntingtin could regulate the assembly of other supramolecular complexes that are involved in various cell pathways, as suggested by the diverse nature of its interactors (Kaltenbach et al, 2007). For example, huntingtin interacts with the β-catenin destruction complex and thus participates in the tight regulation of the steady-state levels of β-catenin (Godin et al, 2010b; Kaltenbach et al, 2007). This might be crucial to regulate the Wingless/Wnt signalling pathway, known for its central role during development and adulthood. Thus, the functions attributed to huntingtin so far are important cellular processes in the early stages of development and adulthood, and contribute as initial or secondary disease mechanisms to several neurodegenerative disorders. This might not be a coincidence!Finally, the scaffold nature of huntingtin might be important for histogenesis in general and explain the widespread abnormalities observed in Huntington disease. A high level of huntingtin is found in the testes and one of the peripheral manifestations of the disease is testicular pathology, with a reduced number of germ cells and abnormal seminiferous tubule morphology (van Raamsdonk et al, 2007). Testes require functional intracellular transport for their normal development, and asymmetrical division is particularly important for germline stem-cell maintenance. Thus, an abnormal developmental programme induced by defective huntingtin function would alter cells and, thereby, the homeostasis of the tissues expressing this protein.Several other disorders are caused by the toxic presence of an abormal polyglutamine expansion. These ‘polyglutamine diseases'' have this mutation in common; however, the mutated proteins are unrelated and the disorders are phenotypically distinct, affecting different brain regions and neurons. A defect in the function of the mutated proteins explains the separate mechanisms of neuronal degeneration observed. Huntington disease is a dominant disorder, but the vision of it as a gain-of-function disease with loss-of-function manifestations could be outdated. The situation seems to be more complicated, and most patients express not only one copy of the mutant huntingtin, but also half the amount of the wild-type protein. It is time to rethink the idea that studying huntingtin protein is irrelevant to Huntington disease. In the light of recent advances in the understanding of its function, one might even suggest that taking developmental biology into account could provide new insight into the pathological mechanisms of this so far incurable adult-onset disorder.     

Inherited CAG.CTG allele length is a major modifier of somatic mutation length variability in Huntington disease

Huntington disease (HD) is associated with an unstable trinucleotide CAG.CTG repeat expansion. Although the repeat length is inversely correlated with the age-at-onset of symptoms, variability between patients who have inherited the same HD repeat length clearly suggests that other factors influence this aspect of the disease. As repeat length profiles in somatic tissues suggest that repeat length gains may contribute to both the tissue-specificity and progressive nature of HD pathogenesis, genetic modifiers of mutation length variability may therefore influence the age-at-onset of the disease. Using a sensitive single molecule-PCR assay we show that HD mutation length profiles in buccal cell DNA vary from individual to individual. The resulting data provide the first quantitative evidence that inherited CAG.CTG repeat length has a major influence on somatic CAG.CTG repeat length variation. In addition, we confirm that further environmental and/or genetic modifiers of repeat length variation exist and discuss the implications that our results may have on understanding the factors that influence severity and age-at-onset of Huntington disease symptoms.     

History of genetic disease: the molecular genetics of Huntington disease - a history

The Huntington disease gene was mapped to human chromosome 4p in 1983 and 10 years later the pathogenic mutation was identified as a CAG-repeat expansion. Our current understanding of the molecular pathogenesis of Huntington disease could never have been achieved without the recent progress in the field of molecular genetics. We are now equipped with powerful genetic models that continue to uncover new aspects of the pathogenesis of Huntington disease and will be instrumental for the development of therapeutic approaches for this disease.     

Mitochondria and Neurodegeneration

Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. However, despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question “is mitochondrial dysfunction a necessary step in neurodegeneration?” is still unanswered. In this review, we highlight some of the major neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington’s disease) and discuss the role of the mitochondria in the pathogenetic cascade leading to neurodegeneration.     

DNA Repair Mechanisms in Huntington’s Disease

The human genome is under continuous attack by a plethora of harmful agents. Without the development of several dedicated DNA repair pathways, the genome would have been destroyed and cell death, inevitable. However, while DNA repair enzymes generally maintain the integrity of the whole genome by properly repairing mutagenic and cytotoxic intermediates, there are cases in which the DNA repair machinery is implicated in causing disease rather than protecting against it. One case is the instability of gene-specific trinucleotides, the causative mutations of numerous disorders including Huntington’s disease. The DNA repair proteins induce mutations that are different from the genome-wide mutations that arise in the absence of repair enzymes; they occur at definite loci, they occur in specific tissues during development, and they are age-dependent. These latter characteristics make pluripotent stem cells a suitable model system for triplet repeat expansion disorders. Pluripotent stem cells can be kept in culture for a prolonged period of time and can easily be differentiated into any tissue, e.g., cells along the neural lineage. Here, we review the role of DNA repair proteins in the process of triplet repeat instability in Huntington’s disease and also the potential use of pluripotent stem cells to investigate neurodegenerative disorders.     

Erythrocyte membrane alterations in Huntington disease: Effects of γ-aminobutyric acid

The interaction of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) with erythrocyte membranes from patients with Huntington disease and normal controls has been studied by electron spin resonance. GABA affects the physical state of erythrocyte membrane proteins in control and Huntington disease differently. In addition, after exposure of spin-labeled Huntington disease erythrocyte membranes to 0.1 mM GABA, the relevant electron spin resonance parameters reflecting the physical state of membrane proteins are indistinguishable from those of untreated control membranes. These findings support the concept that this disease is associated with a generalized membrane defect.     

A family with Huntington disease and reciprocal translocation 4;5.

We report the clinical and cytogenetic findings in a family in which a balanced reciprocal translocation between the long arm of chromosome 4 and the short arm of chromosome 5 is segregating together with Huntington disease in 2 generations. In situ hybridization studies revealed that the linked human DNA marker is located on the short arm of the normal and translocated chromosome 4 in the region 4p16. The association between Huntington disease and the translocation in this family may represent a chance occurrence. However, it is also possible that there is an undetected rearrangement of DNA on chromosome 4 involving the gene for Huntington disease but not affecting the site of the linked marker. Finally, the likelihood that this represents heterogeneity cannot be excluded.     

No evidence for increased oxidative damage to lipids, proteins, or DNA in Huntington's disease

It has been proposed that mitochondrial dysfunction and excitotoxic mechanisms lead to oxidative damage in the brain of Huntington;s disease patients. We sought evidence that increased oxidative damage occurs by examining postmortem brain material from patients who had died with clinically and pathologically diagnosed Huntington's disease. Oxidative damage was measured using methods that have already demonstrated the presence of increased oxidative damage in Parkinson's disease, Alzheimer's disease, and senile dementia of the Lewy body type. No alterations in the levels of lipid peroxidation (as measured by lipid peroxides and thiobarbituric acid-malondialdehyde adducts) were found in the caudate nucleus, putamen, or frontal cortex of patients with Huntington's disease compared with normal controls. Similarly, there were no elevations in the levels of 8-hydroxyguanine or of a wide range of other markers of oxidative DNA damage. Levels of protein carbonyls in these tissues were also unaltered. Our data suggest that oxidative stress is not a major component of the degenerative processes occurring in Huntington's disease, or at least not to the extent that occurs in other neurodegenerative disorders.     

Implant‐supported overdenture in an elderly patient with Huntington’s disease

doi:10.1111/j.1741‐2358.2009.00343.x
Implant‐supported overdenture in an elderly patient with Huntington’s disease Huntington’s disease is a hereditary, progressive, neuro‐degenerative disorder characterised by increasingly severe motor impairment, cognitive decline and behavioural manifestations leading to functional disability. Dyskinesia and hyperkinesia of the tongue and the peri‐oral musculature make it impossible for the patient to wear a conventional complete denture, despite an adequate alveolar ridge. The present paper reports on a patient with Huntington’s disease who was rehabilitated with a mandibular overdenture supported by two endosteal implants. One year follow‐up examination showed that the prosthesis was stable and there was considerable improvement in the patient’s masticatory function.     

Viral susceptibility of skin fibroblasts from patients with Huntington disease.

Cultured skin fibroblasts from patients with Huntington disease (HD) and age-matched controls were tested for susceptibility to vesicular stomatitis virus (VSV) and transformation by Kirsten mouse sarcoma virus (KiMSV). The HD and control cells could not be distinguished on the basis of viral replication, plaque morphology, virus yield, or susceptibility to transformation by KiMSV. These findings suggest that the HD gene product, if expressed within peripheral tissue, does not selectively alter or interfere with viral replication.     

Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease

Inhibition of polyglutamine-induced protein aggregation could provide treatment options for polyglutamine diseases such as Huntington disease. Here we showed through in vitro screening studies that various disaccharides can inhibit polyglutamine-mediated protein aggregation. We also found that various disaccharides reduced polyglutamine aggregates and increased survival in a cellular model of Huntington disease. Oral administration of trehalose, the most effective of these disaccharides, decreased polyglutamine aggregates in cerebrum and liver, improved motor dysfunction and extended lifespan in a transgenic mouse model of Huntington disease. We suggest that these beneficial effects are the result of trehalose binding to expanded polyglutamines and stabilizing the partially unfolded polyglutamine-containing protein. Lack of toxicity and high solubility, coupled with efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases. The saccharide-polyglutamine interaction identified here thus provides a new therapeutic strategy for polyglutamine diseases.     

Disease-specific induced pluripotent stem cells

Tissue culture of immortal cell strains from diseased patients is an invaluable resource for medical research but is largely limited to tumor cell lines or transformed derivatives of native tissues. Here we describe the generation of induced pluripotent stem (iPS) cells from patients with a variety of genetic diseases with either Mendelian or complex inheritance; these diseases include adenosine deaminase deficiency-related severe combined immunodeficiency (ADA-SCID), Shwachman-Bodian-Diamond syndrome (SBDS), Gaucher disease (GD) type III, Duchenne (DMD) and Becker muscular dystrophy (BMD), Parkinson disease (PD), Huntington disease (HD), juvenile-onset, type 1 diabetes mellitus (JDM), Down syndrome (DS)/trisomy 21, and the carrier state of Lesch-Nyhan syndrome. Such disease-specific stem cells offer an unprecedented opportunity to recapitulate both normal and pathologic human tissue formation in vitro, thereby enabling disease investigation and drug development.     

Population-demographic and clinico-genetic characteristics of Huntington chorea in one region of Azerbaijan

The data are presented on prevalence and clinical patterns of Huntington disease in Shamkhor region of Azerbaijan, where about 126.8 thousand inhabitants live. Population, demographic and genealogical data show that high prevalence of Huntington disease in that region is determined by the founder effects, reinforced later by extended reproduction of the population. Linkage analysis using the affected sib-pair method failed to reveal a linkage between Huntington's chorea locus and HLA, AB0, MN systems. Significant probability of linkage to Huntington's chorea locus was calculated for Gc marker.     

Interacting proteins as genetic modifiers of Huntington disease

Huntington disease is caused by polyglutamine expansion in huntingtin, a 350 kD protein that is ubiquitously expressed and widely distributed at the subcellular level. Recently, Kaltenbach et al. identified a large collection of novel huntingtin-interacting proteins, several of which modify mutant huntingtin toxicity in Drosophila. Thus, the interaction of mutant huntingtin with certain protein partners can influence its toxicity and therefore the severity and/or progression of Huntington disease.     

Ethical and legal dilemmas arising during predictive testing for adult-onset disease: the experience of Huntington disease.

The goal of predictive testing is to modify the risk for currently healthy individuals to develop a genetic disease in the future. Such testing using polymorphic DNA markers has had major application in Huntington disease. The Canadian Collaborative Study of Predictive Testing for Huntington Disease has been guided by major principles of medical ethics, including autonomy, beneficence, confidentiality, and justice. Numerous ethical and legal dilemmas have arisen in this program, challenging these principles and occasionally casting them into conflict. The present report describes these dilemmas and offers our approach to resolving them. These issues will have relevance to predictive-testing programs for other adult-onset disorders.