Brain, Vol. 125, No. 3, 656-663,
March 2002
© 2002 Guarantors of Brain
Neuronal intranuclear inclusions in SCA2: a genetic, morphological and immunohistochemical study of two cases
1 Hereditary Ataxia Research Group, Imperial College, 2 Departments of Neurology and 3 Neuropathology, Institute of Neurology, University College London, London, UK and 4 Clinica Neurologica 2, Università di Padova, Italy
Correspondence to: Francesco Scaravilli, Department of Molecular Pathogenetics, Division of Neuropathology, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK E-mail: F.Scaravilli{at}ion.ucl.ac.uk
Received August 23, 2001. Revised October 16, 2001. Accepted October 22, 2001.
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Spinocerebellar ataxia 2 (SCA2) belongs to the family of autosomal dominant cerebellar ataxias (ADCA), a genetically heterogeneous group of neurodegenerative diseases. The SCA2 gene maps to chromosome 12q24 and the causative mutation involves the expansion of a CAG repeat within the coding region of the gene. Pathologically, SCA2 presents as olivo-ponto-cerebellar atrophy (OPCA). We present the cases of a 41-year-old man and a 54-year-old woman who died after a long illness characterized by severe cerebellar ataxia. Diagnosis of SCA2 was confirmed by genetic analysis. The brains were moderately to severely atrophic and atrophy was particularly obvious in the cerebellum and brainstem. Histological examination revealed extreme loss of pontine and olivary nuclei and Purkinje cells, with preservation of the dentate nuclei, and of the pigmented cells in the substantia nigra. The whole spinal cord was also severely affected, with shrinkage of the dorsal columns and reduction in the number of neurones in the motor pool and Clarke’s nuclei. Immunohistochemistry with 1C2 antibody showed granular neuronal cytoplasmic deposits in all the areas examined and widespread intranuclear inclusions, which were particularly numerous in the residual pontine nuclei. Intranuclear inclusions were not considered a feature in SCA2. Our results support the view that intranuclear inclusions are an integral part of the pathology of this mutation.
Keywords: 1C2; nuclear inclusion; polyglutamine; SCAs; spinocerebellar degeneration
Abbreviations: ADCA = autosomal dominant cerebellar ataxia; ßA4 = beta-amyloid precursor protein; DRPLA = dentatorubral-pallidoluysian atrophy; GFAP = glial fibrillary acidic protein; H&E = haematoxylin and eosin; LFB/N = Luxol fast blue/cresyl violet; NI = nuclear inclusion; OPCA = olivo-ponto-cerebellar atrophy; polyQ = polyglutamine; SCA = spinocerebellar ataxia
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Introduction |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive deterioration in gait, speech and limb coordination. To date, seven disease loci have been cloned: spinocerebellar ataxia 1 (SCA1) (Orr et al., 1993
), SCA2 (Imbert et al., 1996; Pulst et al., 1996; Sanpei et al., 1996), SCA3 (Machado–Joseph disease) (Kawaguchi et al., 1994), SCA6 (Zhuchenko et al., 1997), SCA7 (David et al., 1997), SCA8 (Koob et al., 1999), SCA10 (Burgess et al., 2000), SCA12 (Holmes et al., 1999) and SCA17 (Koide et al., 1999).
SCA2 is characterized by progressive gait and limb ataxia, dysarthria, slow saccadic eye movements, supranuclear ophthalmoplegia and depressed or absent tendon reflexes. Intellectual impairment, varying from mild to severe, has also been described in some families (Dürr et al., 1995; Giunti et al., 1998). The variable age of onset (8–80 years) and severity of the disease are attributed to the underlying mutation, which is a CAG trinucleotide repeat expansion within the coding sequence of the SCA2 gene. Normal alleles contain between 15 and 31 repeats, which increase to between 33 and 63 in pathological cases. Larger disease alleles are associated with an earlier age of onset and more severe clinical manifestations. The gene encodes a novel protein (ataxin-2) of 
140 kDa.
Pathological changes are widespread, but are particularly severe in the cerebellar cortex, pontine nuclei and inferior olives. Indeed, the disorder has been labelled olivo-ponto-cerebellar atrophy (OPCA). Moreover, Dürr et al. (1995) have emphasized the striking discrepancy in their patients between the severe pathological involvement of the substantia nigra and the lack of parkinsonian signs. Spinal cord changes include atrophy and myelin pallor in the posterior columns (Orozco et al., 1989; Dürr et al., 1995). The spinocerebellar tracts are described as normal (Dürr et al., 1995) or moderately demyelinated (Orozco et al., 1989) and the Clarke’s columns and spinal motor neurones are reported as mildly to moderately affected.
Ataxin-2 is expressed in the cytoplasm of most tissues, including brain, with the exception of lung and kidney (Imbert et al., 1996; Pulst et al., 1996; Sanpei et al., 1996). In nerve cells it is most abundant in Purkinje cells, both in normal and SCA2 individuals; however, its expression is greatly increased in the latter (Huynh et al., 1999). Intranuclear inclusions (NIs), a characteristic feature of a number of these disorders, such as dentatorubral-pallidoluysian atrophy (DRPLA) (Igarashi et al., 1998), Huntington’s disease (Davies et al., 1997), SCA1 (Duyckaerts et al., 1999), SCA3 (Paulson et al., 1997) and SCA7 (Holmberg et al., 1998), were considered absent in SCA2 (Dürr et al., 1995; Huynh et al., 1999). A recent study (Koyano et al., 1999) showed inclusions, albeit in a small percentage of neurones (1–2%), in SCA2. Here we describe widespread neuronal NIs in the CNS of two patients suffering from this disease.
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Patients and methods |
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Patients
Patient 1
Patient 1 was born in 1959 in the USA and was resident in the UK. Since 1984 he had noticed difficulty with coordination of the limbs. Ataxia was formally diagnosed in 1987, although he had been slightly unsteady for the whole of his life. During a hospital admission in 1986 for abdominal pains, the patient had undergone urethral dilatation for urinary frequency, which deteriorated further in 1990. During a subsequent hospitalization, MRI revealed brainstem and cerebellar atrophy. The patient stopped working in 1991 because of the deterioration of the ataxia; swallowing problems supervened and worsened in 1999. Shortly before death, he became unable to speak and he died in February 2000. The cause given was bronchopneumonia. His sister, still alive at the time this report was written, is suffering from a similar disorder. Both the father and grandfather suffered from a similar ailment; the former died in his 40s of tuberculosis; in the latter, assessment of the disorder was made difficult by a co-existing alcohol problem.
Patient 2
Patient 2 began to notice difficulty in maintaining her balance at the age of 24 years. At 28 years her gait became ataxic, her hands clumsy and her speech slurred. There were momentary episodes of vertigo and altered consciousness, which were thought to be epileptic. There were no sphincter or autonomic disturbances. On examination, she showed marked limitation of the conjugate upward gaze, with no nystagmus, and severe cerebellar deficit involving the arms and legs with ataxic gait. Reflexes were present with flexor plantars and there was no sensory deficit. On a subsequent examination at age 54 years (shortly before her death), the patient appeared progressively agitated with gross dysarthria, dystonia and behavioural changes; her intellectual capacities appeared considerably blunted. A CT scan revealed severe ventricular dilatation. The same disease affects both her two children, with onset at 28 and 30 years.
Genetic analysis
Patient 1
DNA extracted from frozen brain using standard methods was investigated for the SCA2 mutation by PCR (polymerase chain reaction) using oligonucleotide primers flanking the CAG repeat motif, as described by Pulst et al. (1996). The alleles were sized accurately by automated sequencing on an ABI Prism 377 DNA sequencer.
Patient 2
No DNA could be amplified from the patient’s brain, which had been fixed in 10% buffered formaldehyde; the diagnosis was established in her two children, using PCR according to the method by Giunti et al. (1998).
Neuropathology and immunohistochemistry
Half of the brain and the whole spinal cord from Patient 1 and the whole brain and spinal cord of Patient 2 were fixed in 10% buffered formalin for 4 weeks. Blocks from representative regions of the cerebral and cerebellar hemispheres, including the deep grey nuclei, midbrain, brainstem and spinal cord, were processed for embedding in paraffin wax. Sections 5 µm thick were stained with routine and immunohistochemical methods. The former included haematoxylin and eosin (H&E), Luxol fast blue/cresyl violet (LFB/N), Bielschowsky silver impregnation and periodic acid–Schiff. The latter included the use of the following antibodies: anti-GFAP (glial fibrillary acidic protein) (Dako, UK; 1 : 400), anti-tau (Dako; 1 : 500), anti-ubiquitin (Dako; 1 : 500), anti-
-synuclein (gift from the Institute of Psychiatry, London; 1 : 1000), anti-beta-amyloid precursor protein (ßA4) (Dako; 1 : 100) and 1C2 (Chemicon Int.; 1 : 1000). The following pretreatments for the retrieval of all antigens except tau protein were applied: (i) microwave heating was used for GFAP, ubiquitin and 1C2; (ii) formic acid pretreatment and formic acid plus microwave heating were used for -synuclein and ßA4, respectively.
Morphometric studies
The degree of cell loss and reactive gliosis in the various regions of the brain was assessed by semiquantitative methods and graded as mild (+), moderate (++) and severe (+++). Neuronal loss in the spinal cord was evaluated using alternate serial 10 µm sections, stained with LFB/N, of the cervical, thoracic and lumbar cord. The nucleoli of the motor neurones in lamina IX, the Clarke’s and intermediolateral nuclei on both sides of the cord were counted. Results of the counts for each group of nerve cells were pooled and the total was divided by the number of sections counted and then divided by two to obtain the average number of cells per level in each side of the cord. Similar spinal cord levels of three normal individuals were used as age-matched controls. The figures in Table 2 are means of these three individuals at each level.
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Results |
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Genetic analysis
Patient 1
Expansion of the SCA2 CAG repeat motif was detected in the patient. DNA sequencing demonstrated a normal allele of 22 repeats and an expanded allele of 43 repeats.
Patient 2
Both children of this patient showed SCA2 expansions in the pathological range, with 44 and 43 CAG repeats, respectively.
Neuropathology
The weights of the whole brain in Patients 1 and 2 were 1120 and 890 g, respectively; the brainstem and cerebellum weighed 80 g in Patient 1 and 100 g in Patient 2. The cerebral hemispheres were globally reduced in volume with atrophic gyri and widened sulci (Fig. 1A). The bulk of the cortex, white matter and deep grey nuclei was reduced proportionally. The following regions were affected most severely: the substantia nigra, which was extremely pale (Fig. B); the cerebellar folia and subjacent white matter, with relative sparing of the dentate nucleus (Fig. C); the basis pontis (Fig. D) and inferior olives, with preservation of the loci coerulei. In the spinal cord there was reduction of both lateral and dorsoventral diameters, particularly the latter.
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Histological examination
The appearance of the CNS was similar in the two patients. In the Purkinje cell layer (Fig. 2A), substantia nigra (Fig. B) and basis pontis (Fig. C), the vast majority of neurones had disappeared. In the inferior olives virtually all nerve cells were absent. The degree of nerve cell loss and reactive gliosis in the various regions of the cerebral and cerebellar hemispheres and brainstem is shown in Table 1. Spinal cord neurones were severely reduced in number and size in the lamina IX and in the Clarke’s nucleus and moderately so in the intermediolateral column. Results of the quantitative evaluation of the loss are shown in Table 2. In the gliotic dorsal columns, axons appeared rather sparse and myelin staining was consequently pale. No NIs could be seen.
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Immunohistochemistry
The neuronal loss was accompanied by a proportional degree of glial reaction, as highlighted by GFAP. Staining with anti-tau, anti-
-synuclein and anti-ßA4 antibodies was negative. Anti-ubiquitin antibody was positive in the cytoplasm of an occasional neurone in the cerebellar dentate nucleus (Fig. 2D) and of a few cells in the basis pontis. Furthermore, in Patient 1, NIs were seen in the cortex (Fig. 2E) and in 4% of neurones in the basis pontis. In Patient 2, a few NIs were seen in the cortex and in a number of subcortical locations, including 9% of the pontine neurones (Fig. 2F), but not the cerebellum.
1C2 antibody revealed cytoplasmic and NIs in both patients. The former were seen in neurones and glial cells. In neurones they were ubiquitous and had appearances ranging from sparsely (Fig. 2G) or coarsely (Fig. 2H) granular to globose (Fig. 2I). They were particularly numerous in the cerebral cortex, putamen, globus pallidus, cerebellar dentate, pigmented nuclei, basis pontis and residual neurones of the spinal cord. Glial inclusions appeared granular (Fig. 2J) and variously distributed; in the inferior olive, where virtually no nerve cells were seen, they were particularly numerous. NIs were only present in cells with cytoplasmic staining. A few of them were seen sparsely in the cerebral cortex (Fig. 2K) and occasionally in the putamen claustrum (Fig. 2L), the raphe of the midbrain, the nucleus of the tractus solitarius (all in Patient 1) and, in Patient 2, the locus coeruleus (Fig. 2M). NIs were not seen in any cerebellar neurone. They were round and sharply demarcated, varied in diameter from 2 to 6 µm and were stained intensely. They were seen in 20% of the residual cells of the basis pontis in one patient and in 15% of these cells in the other patient (Fig. 2N). 1C2 immunostaining appeared also as sparsely granular and seemingly extracellular staining and in an occasional nerve cell process in the cortex. Neither ubiquitin- nor 1C2-positive staining was seen in control samples of brain and cord.
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Discussion |
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The patients described here suffered from a familial form of cerebellar ataxia with an autosomal dominant pattern of inheritance. Genetic studies established that the disorder in Patient 1 and in the two children of Patient 2 was SCA2. SCA2 is associated with an expanded polyglutamine-encoding CAG trinucleotide repeat within a novel gene of unknown function (Imbert et al., 1996
; Pulst et al., 1996; Sanpei et al., 1996). The patients presented with late-onset (>20 years) disease, at 28 and 24 years, respectively (Harding, 1982). In both patients, the disorder began with gait ataxia. Dysarthria appeared rather late; cognition remained intact in Patient 1, whilst Patient 2 was reported as ‘blunted’. According to Harding (1982), dementia has a low incidence in patients with late-onset disease.
The main pathological findings in the two patients were similar to those described by others (Orozco et al., 1989; Dürr et al., 1995; Estrada et al., 1999). Macroscopically, they add up to OPCA together with diffuse brain atrophy. The extent of atrophy in Patient 1 was similar to that (20–30%) reported by Orozco et al. (1989) and Huynh et al. (1999); in Patient 2, who survived 26 years after the onset of the illness, it was more in keeping with the figures (40–50%) quoted by Dürr et al. (1995). The moderate reduction in dorsal root ganglion cells described by Estrada et al. (1999) suggests that this loss could contribute to the atrophy of the dorsal columns; this mechanism is similar to that suggested in Friedreich’s ataxia (Hughes et al., 1968).
With regard to the condition of the neurones in the spinal cord, including motor cells, Orozco et al. (1989) described motor neurones as smaller than normal and decreased in number. Dürr et al. (1995) reported mild nerve cell loss in the ventral horn as well as in Clarke’s nuclei and the intermediolateral columns. Our figures are in keeping with the results of a morphometric study by Estrada et al. (1999), showing up to 77% cell loss both in motor neurones and Clarke’s columns.
The main aim of this study was to investigate the presence, regional distribution and cellular localization of polyglutamine (polyQ) aggregates in the CNS of patients with genetically confirmed SCA2. In contrast to previous studies (Huynh et al., 1999, 2000; Shibata et al., 2000), we found that NIs are not only present in SCA2 but are widespread. Our findings support the view of Koyano et al. (1999), the only other research group to date to suggest that NIs are a feature of SCA2. We found a regional distribution of inclusions similar to that reported by Koyano et al. (1999), but a much higher density (up to 25% versus 1–2% of surviving neurones). It is known that the number of visible NIs in individual cases correlates with the length of the mutated CAG/polyQ tract (Becher et al., 1998). Whether the presence of a much shorter polyQ expansion in the patients reported by Koyano et al. (1999) accounted for the very low frequency of NIs in their study is not clear, since they did not state the number of repeats.
A possible explanation of the difference between our results and those of Huynh et al. (1999) could be the epitope positions of the antibodies used: the monoclonal antibody 1C2, used by us, is raised against the polyglutamine stretch within the TATA-binding protein, which also recognizes the expanded polyglutamine domain of ataxin-2 and other mutant polyglutamine proteins (Trottier et al., 1995). On the other hand, SCA2B, used by Huynh et al. (1999), detects the ataxin-2 C-terminal of a putative caspase site, which is also downstream of the polyQ tract. It is therefore possible that SCA2B failed to detect the potential aggregate-forming polyQ-containing N-terminal fragment of ataxin-2 if cleavage by caspase-3 occurred prior to nuclear translocation of the normally cytoplasmic protein. However, this would not explain the different results obtained by Koyano et al. (1999) and Huynh et al. (1999): the former group obtained comparable results using 1C2 and 15F6, the latter antibody being directed against an epitope close to that detected by the SCA2B antibody. A more plausible explanation would be that the investigations by Huynh et al. (1999, 2000) and Shibata et al. (2000) were confined to the cerebellum, a region in which all groups agree that NIs are not seen.
Huynh et al. (1999) postulated that the lack of SCA2 NIs could be the result of the polyglutamine tract in SCA2 being shorter than in other SCAs and they suggest that the pathogenesis of SCA2 may be different from that of other related disorders. Notwithstanding the known correlation between numbers of visible NIs and the length of the mutated CAG/polyglutamine tract mentioned above, we have now demonstrated that NIs are a feature in SCA2 neurones. However, their absence in the residual Purkinje cells is puzzling, considering that the cerebellum is one of the major sites of degeneration in SCA2. Although the relationship between NIs and cell loss is still not understood, we share the conclusion of Saudou et al. (1998) that inclusions and cell loss are most probably two unrelated phenomena, although the former may play a pathogenic role in the late stages of the disease (Chai et al., 1999).
The localization of NIs in SCA2 correlates with that seen in SCA7 (Holmberg et al., 1998), but differs from that in Huntington’s disease (DiFiglia et al., 1997), in which inclusions are seen only in areas affected by the disease. With regard to SCA1, the reports by Skinner et al. (1997) and Duyckaerts et al. (1999) give contradictory results in that the former did not, whilst the latter did, detect NIs in regions other than those affected. SCA3 resembles Huntington’s disease; however, Paulson et al. (1997) reported inclusions also in the inferior olives, a region not affected by cell loss (Coutinho et al., 1982).
Our observation of 1C2 immunoreactivity in the cytoplasm of glial cells bears some similarities to the finding by Huynh et al. (1999) of stronger labelling with anti-ataxin-2 antibodies in patients than in controls. Weak immunoreactivity to androgen receptor antibodies was detected by Li et al. (1998) in the nucleus of astrocytes and oligodendrocytes in spinal and bulbar muscular atrophy. NIs were also described by Hayashi et al. (1998) in cells considered to be astrocytes in patients with DRPLA. These inclusions were ubiquitin-positive and a small number of them also reacted with a specific anti-DRPLA protein antibody. Our inclusions, however, did not stain with anti-ubiquitin antibody. Although the significance of these deposits is uncertain, they confirm the widespread involvement of neuroectodermal cells in SCAs, as emphasized also by the results by Paulson et al. (1997) in SCA3.
Our results of immunostaining with anti-ubiquitin antibody showed fewer inclusions than revealed by 1C2. In areas where the density of the inclusions could be established by morphometric analysis, such as the pons, the number of ubiquitin-positive inclusions in Patients 1 and 2 amounted to 20 and 60%, respectively, of those stained by 1C2. Ubiquitination is known to be part of the normal proteolytic cellular pathway. However, when it occurs in pathological structures, it is thought to be related to misfolding, aggregation or abnormal protein degradation (Lowe et al., 1993; Galvin et al., 1999). Saudou et al. (1998) suggest that, by surrounding the inclusion, ubiquitin may try to counteract the toxic effect of the mutant protein. Whilst the paper by Koyano et al. (1999) does not mention the density of ubiquitin-positive inclusions, it seems to imply that all those that are SCA2-positive are also ubiquitinated. Similarly, in SCA3, Chai et al. (1999) found that ubiquitin labelled essentially all nuclear inclusions; moreover, Saudou et al. (1998) state unequivocally that huntingtin-positive NIs were never found to be ubiquitin-negative. This is in contrast to both our cases and to the findings of Holmberg et al. (1998) and DiFiglia et al. (1997), both of whom found fewer ubiquitin-positive NIs than 1C2 and anti-huntingtin-positive NIs in SCA7 and Huntington’s disease, respectively. The latter authors suggest that the lower number of ubiquitin- than huntingtin-positive NIs indicates incomplete proteolysis.
In conclusion, in both our patients NIs were present in many regions of the CNS and were particularly numerous in the pons. These results support the view that NIs are an integral part of the pathology of this mutation.
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Acknowledgements |
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We wish to thank Mr Steve Durr for photographic assistance. The work was supported by Ataxia UK (J.T.P.) and by a grant from the Joint Research Advisory Committee of the NHNN and ION, UCL, London (O.A.).
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