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disease 3.1.3. Huntington’s



  • disease 3.1.3. Huntington’s
  • Clinical utility gene card for: Huntington's disease
  • 1. Disease characteristics
  • Huntington's disease (HD) (Huntington's chorea, Huntington disease) . How is the cost effectiveness of alternative diagnostic methods to. Disease Primer Molecular Biology and Genetics of Huntington Disease (HD) Signs and Symptoms Biomarkers. Huntington's disease (HD) is a prototypical neurodegenerative disease in which there is selective neuronal degeneration, .. α-Tocopherol (Vitamin E).

    disease 3.1.3. Huntington’s

    In the acute phase of reaction, astrocytes also reexpress intermediate filaments significant for glial precursors—nestin and vimentin e. NG2 glia polydendrocytes or synantocytes represent a fourth type of glia in the CNS e. They exist abundantly in both grey and white matter of the mature CNS in rodents as well as human. They constitute the major group of cells undergoing mitosis in the adult rodent brain and are almost as numerous as astrocytes [ 42 ].

    NG2 cells are primarily described as the precursors of myelinating oligodendrocytes OLPs. However, many of the NG2 cells remain in the NG2-positive state for a significant time and have a unique capacity to communicate with nearby cells, forming multiple contacts with astrocytes, microglia, oligodendrocytes, and even neurons [ 43 ].

    In human brain, significant morphological changes related to the progression of pathology were studied particularly in multiple sclerosis and gliomas [ 44 ]. Microglia, the immunocompetent highly motile cells of the CNS, are extremely plastic and undergo a variety of structural changes based on their location and current role [ 45 ].

    In the grey matter, the most frequent is ramified form, which express protein Iba1 ionized calcium-binding adapter molecule 1 also known as AIF-1 allograft inflammatory factor 1. The density of this marker significantly increases with activation of cells. It is obvious that the activation of microglia is a basic mechanism in the defence of the CNS, also in relation to neurodegenerative processes e.

    Although the role of microglia in neurodegeneration is still controversial, it is evident that in human brain they are activated in early stages of NDP of different phenotype, primarily in HD e. It is possible that microglia transform to phagocytes and target neurons as the disease progresses but appear to be dysfunctional with increasing amounts of ingested debris [ 48 ]. It is commonly known that the neurodegenerative process of HD phenotype is a chronic process, morphologically characterized by the progressive degeneration of neurons, principally in the striatum, but gradually affecting almost all parts of the brain.

    This results in a reduction of grey matter and brain atrophy with compensatory enlargement of the lateral brain ventricles. Nevertheless, also as the second component of the brain parenchyma, the glial cells play an irreplaceable role in this process.

    The reaction of astrocytes to any damage of the CNS parenchyma in a sense of their conversion into the reactive intensely GFAP-positive subset is well known already for long time.

    Although the participation of other types of glial cells, particularly of microglia and NG2 glia, in neurodegenerative process has been studied in last two decades, the histopathological interrelations among all above-mentioned cell types have not been well described yet.

    Moreover, the validation of existing transgenic rat model of HD51 from this point of view is still lacking. The clinical features of HD described in autopsy records were characteristic for the given stages in all three patients.

    However, detailed neurological records or results of genetic testing were not available because old archival material was used. The severity of striatal histopathological changes was graded grades 0—4 according to Vonsattel and coauthors [ 2 ]. Paraffin blocks of brain tissue from autopsies were taken from the neostriatum the caudate nucleus and putamen at the level of the globus pallidus and at the level of the nucleus accumbens.

    The transcardial perfusion with fixative solution under deep anaesthesia followed by postfixation for 3 days or 2 hours, resp. After postfixation, the brain hemispheres were separated and processed separately. Histological processing was the same for both the experimental material and autopsies. Findings obtained by immunofluorescent detections double-labelling were mostly confirmed by a single antibody detection using peroxidase-antiperoxidase PAP immunohistochemistry on parallel paraffin sections.

    For immunohistochemical detection, deparaffinized and rehydrated sections were used. Sections were then washed and incubated with the appropriate biotinylated secondary antibody Jackson ImmunoResearch Lab. The sequential technique for immunofluorescent double-labelling of antibodies Ab was same for both types of sections.

    The negative control, omitting the primary antibody, was made in each labelling. In order to characterize the progression of NDP in the striatum of tgHD51 rats, we used the quantitative analysis of the median diameter of neuronal nuclei as a marker of proposed significant process in a course of neurodegeneration in tgHD rats; it means the shrinkage of striatal neurons.

    We would like also to determine the onset of significant neuronal degeneration in the striatum of tgHD51 rats and the possible participation of age-related changes. Selected sections were labelled with NeuN antibody, which marks selectively the nuclei of mature neurons, using the PAP immunohistochemical detection. The number of analysed sections was the following: Neuronal nucleus median diameter was obtained from 50 independent measurements in the central area of the striatum on each analysed section.

    Due to possible distortions of the shape of neuronal nucleus in the section, the largest size of the nucleus was considered the nucleus diameter. Each group of rats of the same age was represented by the set of all medians in given group.

    Statistical analyses of the differences between groups were performed using MS Excel Microsoft Corp. Surprisingly, the most distinct changes in striatal grey matter develop by the end of the first year of age probably between 9 and 12 months. The end of the first year represents the turn in the development of morphological changes related to the progression of NDP within the striatum of tgHD51 rats.

    These findings correspond to the course of HD in human brain, where the motor and behavioural changes precede the loss of striatal neurons [ 20 ]. We demonstrate possible parallels between the HD progression in humans and the above-described transgenic rat model and prove the validity of our findings for human HD pathology. The cases demonstrated here represent the sequence of 3 stages grades , grade 3, and grade 4 of the progression of HD in human brain.

    It is almost impossible to dissociate the alterations referring to neurons and glia in a course of NDP because of very close relationship and mutual influence of both main components of striatal parenchyma. However, we would like to stress some features specific for each of them in a course of the development of NDP within the striatum of both rat and human brains. For that reason, we described their involvement in progression of NDP separately.

    When we compare the brains of 2- and 3-month-old, young adult wild-type and tgHD rats, there is no difference in morphology of the striatum. Also lateral brain ventricles are narrow, of the same shape in both mentioned groups Figure 1 a.

    Only in month-old tgHD51 rats appears the identifiable enlargement of lateral ventricles, which documents developing striatal atrophy. The process gradually progresses resulting in prominent widening of lateral ventricles Figure 1 b , with concave medial outline of the striatum in the oldest 22—month-old tgHD rats, which is fully comparable with the progression of HD in human brain. However, with the progression of HD in humans, gradual decrease in number of neurons is significant, particularly in advanced stages of HD grade 3—Figure 4 b and grade 4—Figure 4 c.

    Nuclei of striatal neurons are very characteristic, especially due to their large size and fine loosely arranged chromatin in comparison with significantly smaller nuclei with more densely arranged chromatin of glial cell. Despite the fact that striatal neurons become gradually smaller in course of HD progression compare Figures 3 a and 3 b , such specific features of neuronal and glia nuclei always enable their distinguishing.

    Our immunohistochemical analysis of neuronal nuclei by NeuN shows slow but already significant progression of neuronal degeneration in the striatum from 12 to 24 months of age of tgHD rats Figure 3 b when compared with age-matched controls Figure 3 a and younger tgHD rats.

    The most typical for NDP in tgHD51 rats is a gradual decrease in size of neuronal bodies and nuclei with maintenance of nucleo-cytoplasmic rate , which results in the disintegration and disappearance of affected neurons Figures 2 d — 2 f , ultimately scavenged by microglia Figures 12 b and 12 c. In the human HD brain, grades with approximately 2-year clinical manifestation , the degeneration and loss of neurons were only random; therefore, the loosening of the neuropil has not been apparent yet.

    On the other hand, in grade 3 approximately 8-year clinical history , neuronal degeneration was already obvious Figure 4 b. Depletion of neurons particularly in the CN and putamen Pu accompanied with rarefaction of the neuropil resulted in a reduction of striatal volume and noticeable enlargement of the lateral ventricles. In grade 4 with approximately year clinical diagnosis the entire corpus striatum CN, Pu, and globus pallidus was affected by degeneration of neurons and neuropil resulting in severe striatal atrophy and therefore the concomitant astrogliosis here prevailed Figures 4 c , 10 b , and 10 c.

    The remaining striatal neurons marked by their prominent nuclei gradually became smaller with the progression of NDP, like in the brain of tgHD rats. Additionally, we confirmed that, alike in human HD brain, neuronal degeneration is selective, that is, affecting primarily certain groups of neurons in the striatum of investigated senescent tgHD rats and moreover that age-related changes contribute to final extent of NDP. In order to precisely characterize the progression of NDP within the striatum of tgHD51 rats, our morphological findings were supplemented by quantitative analysis of the diameter of neuronal nuclei labelled with NeuN.

    Also the proportion of age-related changes in this process was assessed. The progression in decrease of the median diameter of neuronal nuclei with age of rats in both wt and tgHD groups of rats is documented by Progress Chart Figure 5 a. In the first two groups of rats, that is, , and 6-month survivors, no differences in the median diameter of NeuN-positive nuclei were detected when compared within the individual group or among the groups.

    Surprisingly, further progression in decrease of the median diameter of neuronal nuclei was not so rapid; however, finally the reduction reached Statistical characteristic of the groups of rats using Box Plot Figure 5 b enables the multiple comparison of the median diameter of neuronal nuclei of the following groups of rats: Differences among three remaining groups are statistically insignificant.

    Moreover, it is potentiated with age-related changes particularly in the oldest animals. Unexpectedly, the transitional amelioration of the process up to slight improvement appeared in both groups wt and tgHD of month survivors. Neuronal degeneration in wt rats can be attributed only to the debit of the aging process; the decrease in size of nuclei was slow and the difference between month-old rats and month-old ones was only 8. Striatal atrophy, in the case of HD, is primarily caused by the degeneration of striatal neurons.

    Of course, the most prominent feature, seen on histological preparations, is a gradual reduction of neuronal bodies marked by the nuclei. Indeed, the reduction in a volume of neuropil is at least of the same importance. Although the rarefaction of neuropil is not based only on the degeneration of this network of neuronal processes and synapses, it demonstrates the progression of such process in both human and rat brains Figures 8 a — 8 d. In addition, we also proved the alterations in a character of synapses.

    In control brains of both rats and humans, synaptophysin-positive synapses are very fine, of uniform size and shape, and plentiful Figures 6 a and 7 a. With the progression of NDP, most of synapses become coarser, more prominent, but of variable size, and some of them are intensely labelled for synaptophysin; consequently, their number gradually decreases Figures 6 b and 7 b.

    Despite different size of synapses in rat Figures 6 a and 6 b and human Figures 7 a and 7 b , the mentioned alterations are of the same character.

    Since the severity of the striatal damage is also influenced by duration of NDP, the changes in morphology of synapses, and particularly the loosening of neuropil, are certainly more prominent in advanced stages of HD in human brain Figure 7 b than in terminal stage of NDP in tgHD rats Figures 6 b and 8 d. Additionally, the alterations in glial component and the ageing-associated changes see Section 3.

    Indeed, the pattern of such process in this basic aspect is the same for both tgHD rats and HD patients. Detection of polyglutamine deposits using polyQ-huntingtin provides interesting findings, which give a complete histopathological picture of HD progression. In wt rats, polyQ detects a normal polyglutamine domain huntingtin encoded by lower number about 35 or less of consecutive glutamine repeats; therefore, only fine polyQ deposits are spread in the nuclei of striatal neurons Figure 8 a.

    In contrast, the pathogenic alleles usually contain 39 or more glutamine repeats, which results in production of mhtt and increased density of intranuclear polyQ expression in relation to the progression of NDP of HD phenotype Figures 8 b — 8 d.

    Surprisingly, using polyQ-huntingtin antibody, neither typical large intranuclear nor neuropil aggregates were seen. Moreover, neurons in adjacent cortex also exhibit intranuclear but more cytoplasmic polyQ deposits; therefore, they are more densely stained in comparison with striatal neurons, particularly in tgHD rats Figures 8 e — 8 g. On the contrary, only few cortical glial cells express polyQ, which corresponds to the absence of typical reactive gliosis in this region.

    It is evident that the developments of changes in glial cell morphology, and certainly also in their function, are conditioned by the intensity and rate of neuronal degeneration in the context of the neuron-glia relationship. Protoplasmic astrocytes are the most numerous component of the striatal parenchyma. The shape of astrocytes changes during the progression of NDP; however specific prominent alterations occur only in human HD brains, where the astrogliosis gradually develops Figures 10 b and 10 c.

    Due to only slow development of neuronal degeneration in the striatum of tgHD rats, the subsequent astrogliosis progresses also slowly—with insignificant onset after 6 months of age of tgHD rats—and becomes more distinct just in 18—month-old animals Figure 9 c. Age-related changes not only are seen in old wt rats, but also participate in progression of reactive gliosis in tgHD rats.

    Less in wt rats or more in tgHD rats developed striatal atrophy is manifested in senescent rats by denser accumulation of smaller nuclei of neurons and glia compare Figures 2 a — 2 c. First of all, in both HD patients and tgHD rats, generation of reactive astrocytes proceeds gradually and slowly, unlike the almost immediate appearance of reactive astrocytes after the acute brain damage.

    Indeed, their bodies are not significantly enlarged hypertrophic ; contrariwise, a part of them also undergoes the degeneration and they are scavenged by microglia Figures 12 c , 13 c , and 13 d. On the contrary, we never found the reexpression of intermediate filaments nestin and vimentin, which is considerable feature of hypertrophic reactive astrocytes after the acute brain damage.

    Although less prominent, expression is also in fine astrocytic processes. In tgHD rats, the coexpression is slightly enhanced in end-feet Figures 10 b and 10 c , unlike significant coexpression in both the cytoplasm of cell bodies and end-feet in human HD brains Figures 10 b and 10 c. They are closely related to the development of myelinating oligodendrocytes, whose precursors are considered. We were interested in their possible alterations related to the progression of NDP in tgHD rats and also in senescence.

    Due to technical reasons particularly the length of formalin fixation and the use of paraffin sections only , we were not able to detect NG2 glia cells in postmortem samples of human brains. In the rat brain, we did not prove any significant changes either in their number or in morphology in a course of the development of NDP, even in ageing process. In all examined samples, they were numerous e.

    They represent a special type of professional phagocytes occurring only in CNS, which are spread out primarily within grey matter Figures 12 a and 13 a , but in lower number they are present also in white matter. In agreement with previous studies we document their upregulation with the progression of NDP, particularly in advanced stages, in both tgHD51 rats and HD brains Figures 12 and 13 , unlike their only slowly growing number in ageing control animals.

    In the oldest 18—month-old wt control rats, their number is evidently higher, which confirms physiological increase of neuronal degeneration in aged animals. This double-staining enables to document the consequence of stages of neuronal degeneration and removal of neurons, including the accumulation of ingested debris inside the microglial cells Figures 12 b and 12 c.

    Indeed, glial cells mainly astrocytes degenerate as well and are scavenged in both rat and human brain under the pathological e. In human brain, in relation to advancing NDP, the growing number of microglia is also observed Figure 13 b , especially in comparison with normal control brains Figure 13 a.

    However, the large number of microglia is present only in relation to degenerated and scavenged neurons; when most of striatal neurons are destroyed i. By contrast, in the Pu of the same sample, degenerated scavenged neurons and therefore also the microglia were still present in a large amount. Using the quantitative analysis, we clearly demonstrated for the first time that the turn point in the progression of neurodegenerative process in tgHD51 rats is before the end of the first year of animal age.

    Then, between 12 and 24 months of age, the further progression is gradual but at a slower rate, resulting in death of many neurons.

    Moreover, we confirmed that the development of NDP within the striatum is accompanied with gradual degeneration of cortical, particularly pyramidal neurons. We also documented significant participation of the glia, of which function in the development of NDP is irreplaceable. This transformation is responsible for alterations in a structure and therefore also in a function of the perivascular glial limiting membrane, loosening of neuropil, and other changes.

    Certainly, the entire process is potentiated by ageing changes. Our results confirm the complexity of the entire process, in which the neuron-glia crosstalk is crucial. The aim of our study was primarily motivated by the absence of histopathological characteristics of chronic neurodegenerative process of HD phenotype in transgenic HD51 CAG rats, which, unlike the other transgenic animal models of HD, survive up to 2 years.

    Moreover, this transgenic model comprises relatively smaller number 51 of CAG repeats. Both mentioned hallmarks create conditions for similarity to the late-onset form of HD. For this reason, we tried to define to which extent is possible to make a parallel between rat tgHD model and real NDP in human HD brain from histopathological point of view. On the other hand, behavioural symptoms were already widely studied on these animals see below. Despite the fact that HD takes place exclusively within human brain and each type of existing animal models is not able to replicate completely mechanisms participating in NDP of the HD phenotype, transgenic models represent a crucial part in the field of the research on HD pathogenesis.

    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. 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.

    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 ]. Accumulation of polyQ within the neurons and inside the neuropil is primarily described in a form of aggregates. Our findings showed fine polyQ-huntingtin-positive deposits within the nuclei of striatal neurons in control wt rats and their increase up to very dense accumulation in course of the progression of NDP in tgHD51 rats.

    PolyQ-huntingtin antibody labels not only expanded polyglutamine mhtt but also wild-type normal huntingtin; therefore the deposits are also present in the brain of control rats.

    Hence, increased density of polyQ expression in tgHD51 rats is related to increased number of glutamine repeats, that is, to the accumulation of mhtt. Htt is particularly not only spread within the cytoplasm of neuronal bodies and dendrites [ 7 ] but also present in the nucleus [ 53 ].

    Mhtt is present in both nuclear and cytoplasmic compartments, extended polyQ aggregated in the cytoplasm and then it is transported to the nucleus [ 54 ]. Increasing concentration of the mhtt in the nucleus accelerates the onset and progression of NDP; however, also extranuclear polyQ might contribute to the initiation of NDP [ 55 ].

    The same but almost exclusively intranuclear polyQ deposits were also found in glial cells in both brain regions. Accumulated mhtt causes the dysfunction of astrocytes, particularly in relation to glutamate uptake, since it decreases the expression of glutamate transporters. A negative test result has potential impact on family planning and lifestyle, eg, on the choice of education alternatives, professions, career planning etc.

    Yes, but invasive prenatal DNA diagnosis is restricted by law in several countries, such as Germany. Pre-implantation diagnosis is technically possible, and it is currently performed, for example, in North America.

    In both, individuals with negative results potentially due to guilt feelings or positive results concerning the mutation in the HTT gene, the diagnosis can lead to depression and to serious consequences. Thus, detailed counselling, sufficient time to consider all the potential consequences and psychotherapeutic accompany are necessary as recommended in the predictive testing guidelines.

    This work was supported by EuroGentest2 Unit 2: JTE declares no conflict of interest. National Center for Biotechnology Information , U. Eur J Hum Genet. Published online Oct 9. Author information Copyright and License information Disclaimer. Josef-Hospital, Bochum , Germany. Index case in that family had been tested: Index case in that family had not been tested: The tested person is clinically affected To be answered if in 1.

    The tested person is clinically unaffected but carries an increased risk based on family history To be answered if in 1. If the test result is positive please describe A positive test result has potential impact on family planning and lifestyle, eg, on the choice of education alternatives, professions, career planning etc. If the test result is negative please describe A negative test result has potential impact on family planning and lifestyle, eg, on the choice of education alternatives, professions, career planning etc.

    If applicable, further consequences of testing In both, individuals with negative results potentially due to guilt feelings or positive results concerning the mutation in the HTT gene, the diagnosis can lead to depression and to serious consequences.

    Acknowledgments This work was supported by EuroGentest2 Unit 2: DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence.

    Prevalence estimates of Huntington disease in Caucasian populations are gross underestimates. Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease. Predictive testing for Huntington disease: Exploring the correlates of intermediate CAG repeats in Huntington disease.

    Huntington's disease as caused by 34 CAG repeats.

    Clinical utility gene card for: Huntington's disease

    Antibodies. .. Huntington Disease's (HD) is one of the most common inherited genetic diseases that HD is also called Huntington chorea, from the. Experimental models of Huntington's disease. Huntington's disease, also termed Huntington chorea is an inherited .. Chemicals for Western blot. Rats transgenic for Huntington's disease (tgHD51 CAG rats), .. Rarefaction of Neuropil and Alterations in Morphology of Synapses.

    1. Disease characteristics


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