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Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions
Introduction
Results
Neuropathology of the SCA7 brain
Immunohistochemistry
Discussion
Material And Methods
Case and control
Immunohistochemistry
Acknowledgements
References
Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions
Autosomal dominant cerebellar ataxia with progressive macular degeneration is caused by a CAG/glutamine repeat expansion in the SCA7 gene/protein. Neuronal intranuclear inclusions were detected in the brain of an early onset SCA7 case with the 1C2 antibody directed against an expanded polyglutamine domain. Nuclear inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7. They were also observed in other brain regions, including the cerebral cortex, not considered to be affected in the disease. Using confocal microscopy we showed that some inclusions were ubiquitinated, but to varying degrees, ranging from <1% in the cerebral cortex to 60% in the inferior olive. In addition, we also observed cytoplasmic staining using the 1C2 antibody, particularly in the supramarginal gyrus, the hippocampus, the thalamus, the lateral geniculate body and the pontine nuclei. These data confirm that the presence of intranuclear inclusions in neurons is a common characteristic of disorders caused by CAG/polyglutamine expansions, but unlike what has been reported for Huntington's disease, SCA1 and SCA3/MJD, in SCA7 the inclusions were not restricted to the sites of severe neuronal loss.
INTRODUCTION
Spinocerebellar ataxia type 7 is a neurodegenerative disorder characterized by neural loss, mainly in the cerebellum and regions of the brainstem and, particularly, the inferior olivary complex (1-3). The disease is caused by an unstable CAG repeat expansion in the 5[prime]-translated region of a gene of unknown function and is associated with marked anticipation (4). The number of CAG/glutamine repeats in the pathological protein varies from 37 to >200 (4-7). SCA7 is the eighth disorder shown to result from a CAG/polyglutamine expansion. The group also includes the dominant ataxias SCA1, SCA2, SCA3 and SCA6, as well as spinal and bulbar muscular atrophy, Huntington's disease (HD) and dentatorubral-pallidoluysian atrophy (8-17). It has been postulated that these disorders result from a common gain-of-function of the expanded polyglutamines (18,19). In most of the other cases examined, as in SCA7 (4), the pathological genes/proteins are widely expressed in the brain and not restricted to the regions affected by disease. It was recently demonstrated, however, in patients suffering from Huntington's disease, SCA1 and SCA3 that intranuclear inclusions develop mainly in neurons of regions that are affected by the disease (20-22). The inclusions stain positively for the corresponding polyglutamine proteins as well as for ubiquitin. Furthermore, lines of HD transgenic mice that exhibit symptoms contain intranuclear inclusions in neurons of brain regions known to be affected in HD, while asymptomatic lines do not (23). The formation of nuclear inclusions precedes the neurological phenotype in the HD animals and has been proposed to represent an important step in the neurodegenerative process (23). Why inclusions form in some brain regions but spare other areas where the mutant protein is expressed at comparable levels is not known. It has been proposed that other factors might be involved in formation of the inclusions and determine their cellular specificity. Recently it was shown that the leucine-rich acidic nuclear protein (LANP) interacts with SCA1. LANP is predominantly expressed in cerebellar Purkinje cells, a primary site of pathology in SCA1 as well as in SCA7 (24). It was also demonstrated that SCA1 and LANP are present in the same subnuclear structures when co-transfected into COS-7 cells.
In this immunohistochemical study in an early onset case of SCA7 we have used antibodies against expanded polyglutamines (1C2) (25) and against ubiquitin. We have found intranuclear inclusions in both spared and affected regions. We have also analyzed the inclusions using an antibody directed against the human homolog of LANP, pp32.
RESULTS
Neuropathology of the SCA7 brain
Gross examination. The brain weighed 1168 g. The inferior olive was small. There was severe atrophy of the cerebellar vermis. The dentate nucleus appeared atrophic. The optic nerve was of normal size. The cerebral cortex was normal. The ventricles were not dilated.
Microscopic examination. In the cerebellum neuronal loss was severe in the Purkinje cell layer, where the Bergmann glia was prominent. Neuronal loss was also marked in the nucleus dentatus. The hilus and the mantle were pale. The superior cerebellar peduncle was atrophic, the inferior cerebellar peduncle was pale and atrophic, but the middle cerebellar peduncle was normal. In the inferior olivary complex neuronal loss was extensive and was associated with a marked astrocytic gliosis. The hilus was pale and the mantle was spared. Moderate neuronal loss and gliosis were also observed in the hypoglossal nucleus. The pyramidal tract was normal, while the median lemniscus was pale. The nucleus gracilis and nucleus cuneiformis were gliotic. The substantia nigra and the locus coeruleus were slightly pigmented; some pigment was seen in the extracellular space, associated with a mild neuronal loss. The thalamus and striatum were normal. Myelin appeared remarkably spared in the optic tract, while the lateral geniculate body was gliotic without prominent neuronal loss. A slight astrogliosis was also noted in the primary visual cortex. The rest of the cerebral cortex appeared normal. The number of neurons in the red nucleus was normal, although it appeared gliotic. Neuronal density was close to normal in the pontine nuclei, which were, however, small in size. The central region of the basis pontis was pale and vacuolar on microscopic examination. Central pontine myelinolysis was diagnosed in relation to the terminal condition of the patient.Immunohistochemistry
1C2 staining in SCA7 brain neurons. With the polyglutamine-specific 1C2 antibody we stained intranuclear inclusions in neurons in several regions of the SCA7 brain (Table 1, Figs 1. A-C and 2. A and B), but not in an age-matched control (data not shown). The intranuclear structures were most frequent in neurons of the inferior olive, the lateral geniculate body and substantia nigra, where 17, 12 and 10% of the neurons respectively contained inclusions (Table 1). In the cerebellum, a severely affected site in SCA7, almost all Purkinje cells were lost and very few nuclear inclusions could be found in those that remained (Table 1). A substantial number of nuclear inclusions could be seen in regions of the cerebral cortex, including the supramarginal gyrus and the insula, even though no obvious neuronal loss was observed in these structures (Table 1 and Fig. 2). The nuclear inclusions were restricted to neuronal cells in all regions examined. Most frequently one inclusion was observed per nucleus, with a mean size of 3 ± 1 µm, but neurons with two nuclear inclusions could also be seen. Cytoplasmic staining was also detected in neurons in some brain regions, including the supramarginal gyrus, hippocampus, thalamus, geniculate body and pontine nuclei, but was not associated with inclusion-like structures and was not restricted to neurons containing nuclear inclusions (Fig. 3A-C). Cytoplasmic staining was not observed in the age-matched control.
Table 1
| Brain region | NII/mm2 | Percent neurons with NII |
Percent ubiquitinated NII |
| Cortex | |||
| Supramarginal gyrus | 25 | 7 | <1 |
| Insula | 16 | 8 | 6.5 |
| Motor cortex | 5.2 | 5 | <1 |
| Visual cortex | 4.7 | 2 | <1 |
| Hippocampus | 4.7 | <1 | <1 |
| Entorhinal cortex | 0 | <1 | <1 |
| Basal ganglia | |||
| Lateral geniculate body | 30.7 | 12 | <1 |
| Putamen | 3.1 | <1 | <1 |
| Pallidum | 0 | <1 | <1 |
| Thalamus | 0 | <1 | <1 |
| Brainstem | |||
| Pontine nuclei | 14.1 | 5 | 15 |
| Inferior olive | 9.9 | 17 | 24 |
| Substantia nigra | 5.7 | 10 | 14 |
| Substantia reticulata | 1.6 | <2 | <1 |
| Tegmentum pontis | 0.5 | <1 | <1 |
| Cerebellum | |||
| Purkinje cells | 5 (1/20) | <1 | |
| Granular cells | 0 | <1 | <1 |
Ubiquitination of SCA7 nuclear inclusions. We also found that some nuclear inclusions in the SCA7 brain stained positively for ubiquitin with an antibody against ubiquitin (Table 1). By confocal immunofluoroscence we confirmed the co-localization of ubiquitin and the expanded polyglutamine protein in the same nuclear inclusions (Fig. 4A-C). The degree of ubiquitination varied in the double stained sections and in six out of 15 randomly examined polyglutamine-positive nuclear inclusions in the inferior olive no ubiquitin could be detected. We also calculated the number of 1C2- and ubiquitin-positive inclusions in adjacent sections of all brain regions examined. In all regions of the cerebral cortex, except the insula, very few if any of the inclusions were ubiquitinated (Table 1).
Figure 1. Neuronal intranuclear inclusions (see arrows) in regions of the brainstem in a juvenile case of SCA7 detected by the polyglutamine-specific mAb 1C2. (A) Inferior olivary complex. Bar 50 µm. (B) Inferior olivary complex. Bar 25 µm. (C) Pontine nuclei. Bar 25 µm. Figure 2. Neuronal intranuclear inclusions (see arrows) in regions of the cerebral cortex in a juvenile case of SCA7 detected by the polyglutamine-specific mAb 1C2. (A) Motor cortex. (B) Supramarginal gyrus. Bar 25 µm. Figure 3. Cytoplasmicstaining of neurons in different brain regions of a juvenile case of SCA7 detected by the polyglutamine-specific mAb 1C2. (A) Hippocampus. (B) Striatum. (C) Cerebellum. Bar 25 µm. Figure 4. Confocal co-immunofluorescence analysis using the polyglutamine-specific mAb 1C2 and anti-ubiquitin on a section of the inferior olive of a juvenile case of SCA7. (A) Polyglutamine-specific mAb 1C2. (B) Anti-ubiquitin. (C) 1C2 and anti-ubiquitin.SCA7 nuclear inclusions do not contain LANP. With an antibody against human LANP, anti-pp32, we determined that LANP was not present in the nuclear inclusions of SCA7 in the inferior olive. However, in selective neurons of the brainstem in both SCA7 and control brains (data not shown) nuclear staining not associated with inclusions could be observed.
DISCUSSION
The mechanism by which proteins with polyglutamine expansions cause neurodegenerative disease is not known. Formation of aggregates by self-association or by interaction with other factors has been proposed. Recent reports describing nuclear inclusions in brains of HD, SCA3/MJD and SCA1 patients (20-22), as well as the data presented in this report, confirm the existence of nuclear inclusions as a common feature of polyglutamine disorders. In this study we demonstrated the presence of neuronal nuclear inclusions in several brain regions of an early onset SCA7 patient, known to carry an expanded allele with 85 CAG repeats. The polyglutamine-specific antibody 1C2 has been demonstrated to specifically recognize polyglutamines of pathological size (25) and has been used to detect the expanded 130 kDa ataxin-7 protein on western blots of protein extracts from the cerebellum of the same patient (26). Whether the nuclear inclusions also contain the normal ataxin-7 protein has not yet been determined.
Unlike nuclear inclusions in HD, SCA1 and SCA3/MJD patients (20-22), which were mainly observed in neurons affected by disease, those in the SCA7 patient were not restricted to regions affected by disease. They were most frequent in neurons of the inferior olive, severely affected in SCA7, but could also be observed at high frequency in brain regions not known to be lesioned in SCA7, including the supramarginal gyrus and the insula. In the cerebellum, another region with extensive neuronal loss, so few Purkinje cells remained that accurate estimation of the frequency of inclusions was impossible. One might also argue that the relative absence of inclusions in highly affected brain regions was due to loss of the neurons. This would not account, however, for the inferior olive, where neuronal loss was severe and intranuclear inclusions were frequent.
Cytoplasmic staining was observed in neurons of regions, such as the supramarginal gyrus, the lateral geniculate body and the pontine nuclei, where intranuclear inclusions were frequent, although not necessarily in neurons containing inclusions. It was also observed, however, in the thalamus, where no inclusions were found and no neuronal loss or gliosis were detected. The presence of 1C2 immunoreactivity in the cytoplasm was unexpected. It has never been reported in other diseases with intranuclear inclusions caused by expanded trinucleotide repeats and our previous studies of SCA7 lymphoblastoid cells by western blot suggested that the expanded ataxin-7 protein is exclusively targeted to the nucleus (25,26). This is apparently not the case in a small subset of neurons.
Ubiquitination of the nuclear inclusions, a common characteristic in all the polyglutamine disorders examined so far (20-22), was also observed in this SCA7 patient. The degree of ubiquitination varied, however. Although ubiquitinated inclusions were frequent in regions of the brainstem where the inclusions were numerous, this was not the case in the insula of the cerebral cortex, although in other cortical structures very few if any ubiquitinated inclusions could be observed. As in our study, DiFiglia et al. also found fewer ubiquitin-positive nuclear inclusions than huntingtin-positive ones when analyzing adjacent brain sections from an HD patient (20). Studies in HD transgenic mice also showed that ubiquitination of the nuclear inclusions is a secondary event that occurs prior to neuronal loss (23). This might explain why numerous non-ubiquitinated inclusions are found in the cerebral cortex, where neuronal degeneration has not yet begun.
There was thus no obvious correlation in the present study between expression of the disease-causing protein, formation of nuclear inclusions in specific neurons and neuronal loss. There is an ongoing search for factors interacting with the disease protein that might determine which cells will die. In a recent paper by Matilla et al. (24) a factor denoted LANP was shown to interact with SCA1 and may confer the cellular specificity of SCA1, since it is expressed in regions of the brain, including the Purkinje cells and the brainstem, where neuronal loss occurs. LANP has also been shown to be recruited to nuclear aggregates by SCA1 in COS-7 cells (24). The pattern of LANP expression also partially overlaps with primary sites of pathology in SCA7. We could not, however, detect any staining of nuclear inclusions in the SCA7 brain with an antibody directed against human LANP (27).
In conclusion, observations on this SCA7 patient confirm that neuronal intranuclear inclusions are a common characteristic of polyglutamine disorders, but we also observed strong cytoplasmic staining of expanded ataxin-7 in neurons of several brain regions. The staining was not, however, restricted to cells containing inclusions and the pathological significance of expanded ataxin-7 in the cytoplasm remains to be determined.
MATERIAL AND METHODS
Case and control
A 6-year-old boy was first examined in the Neurology Department of the Hôpital de la Salpêtrière, Paris. His parents reported learning problems and progressive visual loss at the age of 5. Early development was normal; he walked at 11 months. When examined, moderate cerebellar ataxia, clumsiness of the upper limbs and slight dysarthria were observed. Knee jerks and sensation were normal and the plantar reflex was extensor. Fundoscopy showed pigmentary degeneration. Molecular analysis, performed on blood cells, revealed the presence of an 85 CAG repeat expansion in the SCA7 gene. Three years later the patient refused clinical examination, was able to stand with help, but could no longer walk. He was severely dysarthric and could see shapes but not identify objects. He died at the age of 10 of pneumopathy after several days of coma. The autopsy, performed 24 h after death, was restricted to the brain and did not include the eyes or the spinal cord. The left hemisphere was formalin fixed for 3 weeks, while the right hemisphere was sliced, frozen and kept at -80°C. Representative samples were embedded in paraffin and 8 µm sections were stained with hematoxylin and eosin and by Bodian's silver impregnation.
The control was an 8-year-old boy whose sudden death was attributed to acute cardiac arhythmia. The brain was found macroscopically and microscopically normal.
Immunohistochemistry
Immunohistochemistry was performed with the following primary antibodies: (i) 1C2, a monoclonal antibody previously characterized and shown to recognize polyglutamine proteins with expanded glutamine repeats (25,26), was used at a dilution of 1/4000; (ii) anti-ubiquitin, a polyclonal antibody commercially available from Dako, was used at a dilution of 1/1000; (iii) anti-pp32, a monoclonal antibody commercially available from Transduction Laboratories, was used at a dilution of 1/400. Immunohistochemistry was performed using the avidin-biotin system (Amersham) coupled with appropriate secondary antibodies and DAB as chromogen. Sections were counterstained with Harris' hematoxylin. For confocal microscopy FITC-coupled anti-rabbit (Jackson Immunoresearch) and CY3-coupled anti-mouse (Jackson Immunoresearch) antibodies were used on sections of the inferior olivary complex. Sections were examined with a Leitz TCD laser confocal microscope. To estimate the frequency of co-localization of 1C2 and ubiquitin 15 inclusions from the double stained section were examined.
ACKNOWLEDGEMENTS
We thank Merle Ruberg for critical reading of the manuscript. We are indebted to Marianne Kondo for excellent technical assistance. This work was supported by the Association Française contre les Myopathies (AFM), the VERUM foundation and the Association Française Retinitis Pigmentosa-Retina France. M.H. and G.C. were supported by a post-doctoral fellowship from the Medical Research Council of Sweden (MFR) and a fellowship from the AFM respectively. We thank the family for its participation and Drs du Chazaud, Perin and Pieron for their helpful contributions.
REFERENCES
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|
|
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M. Turmaine, A. Raza, A. Mahal, L. Mangiarini, G. P. Bates, and S. W. Davies Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease PNAS, June 23, 2000; (2000) 110078997. [Abstract] [Full Text]
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H. Shibata, D. P. Huynh, and S.-M. Pulst A novel protein with RNA-binding motifs interacts with ataxin-2 Hum. Mol. Genet., May 22, 2000; 9(9): 1303 - 1313. [Abstract] [Full Text] [PDF]
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C. J. Cummings and H. Y. Zoghbi Fourteen and counting: unraveling trinucleotide repeat diseases Hum. Mol. Genet., April 1, 2000; 9(6): 909 - 916. [Abstract] [Full Text] [PDF]
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A. Wyttenbach, J. Carmichael, J. Swartz, R. A. Furlong, Y. Narain, J. Rankin, and D. C. Rubinsztein Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease PNAS, March 14, 2000; 97(6): 2898 - 2903. [Abstract] [Full Text] [PDF]
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M.-C. Senut, S. T. Suhr, B. Kaspar, and F. H. Gage Intraneuronal Aggregate Formation and Cell Death after Viral Expression of Expanded Polyglutamine Tracts in the Adult Rat Brain J. Neurosci., January 1, 2000; 20(1): 219 - 229. [Abstract] [Full Text] [PDF]
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M. D. Kaytor and S. T. Warren Aberrant Protein Deposition and Neurological Disease J. Biol. Chem., December 31, 1999; 274(53): 37507 - 37510. [Full Text] [PDF]
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M. D. Kaytor, L. A. Duvick, P. J. Skinner, M. D. Koob, L. P. W. Ranum, and H. T. Orr Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7 Hum. Mol. Genet., September 1, 1999; 8(9): 1657 - 1664. [Abstract] [Full Text] [PDF]
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K. Ishikawa, H. Fujigasaki, H. Saegusa, K. Ohwada, T. Fujita, H. Iwamoto, Y. Komatsuzaki, S. Toru, H. Toriyama, M. Watanabe, et al. Abundant expression and cytoplasmic aggregations of {alpha}1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6 Hum. Mol. Genet., July 1, 1999; 8(7): 1185 - 1193. [Abstract] [Full Text] [PDF]
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H. Li, S.-H. Li, A. L. Cheng, L. Mangiarini, G. P. Bates, and X.-J. Li Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice Hum. Mol. Genet., July 1, 1999; 8(7): 1227 - 1236. [Abstract] [Full Text] [PDF]
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S.-H. Li, A. L. Cheng, H. Li, and X.-J. Li Cellular Defects and Altered Gene Expression in PC12 Cells Stably Expressing Mutant Huntingtin J. Neurosci., July 1, 1999; 19(13): 5159 - 5172. [Abstract] [Full Text] [PDF]
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E. Scherzinger, A. Sittler, K. Schweiger, V. Heiser, R. Lurz, R. Hasenbank, G. P. Bates, H. Lehrach, and E. E. Wanker Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington's disease pathology PNAS, April 13, 1999; 96(8): 4604 - 4609. [Abstract] [Full Text] [PDF]
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C.-A. Gutekunst, S.-H. Li, H. Yi, J. S. Mulroy, S. Kuemmerle, R. Jones, D. Rye, R. J. Ferrante, S. M. Hersch, and X.-J. Li Nuclear and Neuropil Aggregates in Huntington's Disease: Relationship to Neuropathology J. Neurosci., April 1, 1999; 19(7): 2522 - 2534. [Abstract] [Full Text] [PDF]
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 D C Rubinsztein, A Wyttenbach, and J Rankin Intracellular inclusions, pathological markers in diseases caused by expanded polyglutamine tracts? J. Med. Genet., April 1, 1999; 36(4): 265 - 270. [Abstract] [Full Text]
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 M. K. Perez, H. L. Paulson, S. J. Pendse, S. J. Saionz, N. M. Bonini, and R. N. Pittman Recruitment and the Role of Nuclear Localization in Polyglutamine-mediated Aggregation J. Cell Biol., December 14, 1998; 143(6): 1457 - 1470. [Abstract] [Full Text] [PDF]
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 J. Hardy and K. Gwinn-Hardy Genetic Classification of Primary Neurodegenerative Disease Science, November 6, 1998; 282(5391): 1075 - 1079. [Abstract] [Full Text]
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M. Turmaine, A. Raza, A. Mahal, L. Mangiarini, G. P. Bates, and S. W. Davies Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease PNAS, July 5, 2000; 97(14): 8093 - 8097. [Abstract] [Full Text] [PDF]
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J. Carmichael, J. Chatellier, A. Woolfson, C. Milstein, A. R. Fersht, and D. C. Rubinsztein Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease PNAS, August 15, 2000; 97(17): 9701 - 9705. [Abstract] [Full Text] [PDF]
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