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Gerstmann-Sträussler-Scheinker disease (GSS) is a hereditary transmissible spongiform encephalopathy associated with prion protein gene mutation P102L. The age of onset is roughly restricted to around the sixth decade; however, it is unclear whether the disease-specific pathology of GSS is already evident in the pre-clinical stage. We had a chance to examine an autopsy case with PRNP P102L mutation. The patient had died at 50 years of age before the clinical symptoms of GSS had appeared; neither neuronal loss, gliosis nor spongiform change was found anywhere in the brain. Immunohistochemistry failed to detect any deposition of prion protein. It is thus considered that amyloid plaque formation in GSS probably develops in a relatively rapid fashion compared with Alzheimer's disease. Although the patient suffered from schizophrenia, no significant pathological changes were detected except for astrocytic inclusion bodies in the cerebral cortex. The nature and significance of the inclusion bodies, which are not observed in patients with GSS, remain unclear.

Abnormal proteolysis may be involved in the motor neuron degeneration of amyotrophic lateral sclerosis (ALS). Although several studies of the ubiquitin-proteasome system in ALS have been reported, the endosome-lysosome system has not been investigated in detail. To clarify the association of neurodegeneration with the endosome-lysosome system in ALS, we examined the pathological expression of cysteine proteases such as cathepsins B, H and L and an aspartate protease, cathepsin D, in the anterior horns of 15 ALS cases and 5 controls. In the ALS cases, cathepsin B immunoreactivity was preferentially decreased in the lateral parts of the anterior gray horns compared with the controls. Its immunoreactivity was increased in the cytoplasm of both shrunken and pigmented neurons but was weak in the neurons containing Bunina bodies. In addition, reactive astrocytes were also immunolabeled with cathepsin B. Cathepsin H and cathepsin L were detected in the cytoplasm of a small number of shrunken and pigmented neurons. Cathepsin D immunoreactivity was strong in the cytoplasm of all motor neurons. The immunoreactivity of cathepsins H, L and D was not significantly different between control and ALS cases. Western blot analysis showed that the 25-kDa activated form of cathepsin B was down-regulated in ALS. Our results suggest that cathepsin B is involved in the motor neuron degeneration in ALS.

Clusterin/apolipoprotein J protein expression in cases with "alpha-synucleinopathies", such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), was investigated using an immunohistochemical method for the labeling of multiple antigens. About 50% of the cortical Lewy bodies in the cases with DLB were immunoreactive for clusterin, whereas brain-stem Lewy bodies in PD and DLB were rarely associated with clusterin. Clusterin was also immunopositive in around 10% of the glial cytoplasmic inclusions (GCIs) in the cases with MSA. Colocalization of clusterin with alpha-synuclein in such bodies or inclusions was clearly correlated with the immunostaining pattern of alpha-synuclein. Subcellular localization of clusterin was almost completely overlapped with the homogeneous immunoreaction of alpha-synuclein in the cortical Lewy bodies; however, clusterin immunoreactivity was not detected in the halo or ring-like structures of the brain-stem Lewy bodies. Furthermore, some Lewy bodies with intense immunoreactivity for clusterin showed only a weak signal for alpha-synuclein. These results suggest that clusterin may modify the formation of alpha-synuclein-positive inclusion bodies such as Lewy bodies and GCIs, through a previously proposed chaperone property of clusterin.

Clusterin (apolipoprotein J), a multifunctional protein involved in amyloidogenesis in Alzheimer's disease, was studied immunohistochemically in both human transmissible spongiform encephalopathies (TSEs) and a mouse model of human TSE. Clusterin immunoreactivity was co-localized with plaque-type deposits but not with punctate-type prion protein (PrP) deposits in human TSEs. On the other hand, clusterin-positive astrocytes were readily demonstrated in the regions of punctate PrP deposits, but not around plaque PrP deposits despite the presence of surrounding astrocytes. Clusterin expression in astrocytes was not disease specific, but the punctate immunoreactivity for clusterin was more prominently demonstrated in TSEs with punctate PrP deposits. Serial analysis in the mouse model of human TSE revealed that clusterin expression in astrocytes was enhanced in the lesions with punctate-type PrP deposits during the disease progression. Thus, the induction of clusterin expression in astrocytes could be more enhanced by punctate-type PrP deposits than by plaque-type deposits. The clusterin molecules co-localized in plaque PrP deposits might be derived not from surrounding astrocytes but from other resources such as cerebrospinal fluid and blood plasma, both of which contain clusterin in significant amounts. Taken together with previously reported findings of the anti-amyloidogenic property in clusterin, our findings suggest that clusterin may be induced as one of the important molecules participating in the neurodegeneration caused by abnormally deposited PrP.

Skeins or skein-like inclusions, one of the two types of ubiquitinated intraneuronal inclusions in amyotrophic lateral sclerosis (ALS), in the neostriatum are not specific to the disease, but it has not yet been determined whether the other, spherical or crescent-shaped inclusions (SCI) are pathognomonic. To clarify this and also to investigate whether the distribution of SCI in particular brain regions is associated with clinical parameters, we examined the occurrence of SCI in the brains of 24 patients with ALS and 94 controls. SCI in the neostriatum were specifically detected in 54% of the ALS cases, but not in any of the controls. No apparent phenotypic denominator, such as disease duration or the occurrence of dementia, correlated to the distribution of SCI in the neostriatum in ALS cases. On the other hand, the occurrence of SCI in both the second and third layers of the parahippocampal gyrus and amygdala was significantly correlated to the presence of dementia in ALS cases. SCI were distributed in association with each other among the parahippocampal gyrus, dentate gyrus of the hippocampus and amygdala, but not between the spinal anterior horn and any non-motor-associated brain regions. These findings suggest that these particular brain regions might be significantly involved in the neurodegenerative process associated with ALS. The relationship of SCI to either ALS pathogenesis or cognitive dysfunction depends on the brain regions in which they are distributed, and this indicates that the neurodegenerative processes in ALS proceed differentially in particular motor-associated and nonmotor-associated brain regions.

We examined the presence of ubiquitin-immunoreactive skein-like inclusions (SLI) in the neostriatum and spinal cord in normal individuals and patients with different neurodegenerative diseases. Ubiquitin-immunoreactive SLI in the neostriatum were observed both in the normal individuals and in the patients with a variety of neurodegenerative diseases. In particular, SLI were frequently seen in normal aged subjects and certain neurodegenerative diseases, such as progressive supranuclear palsy and myotonic dystrophy. In contrast, the occurrence rate of SLI in cases with Pick's disease and multiple system atrophy tended to decrease. On the other hand, SLI in the spinal anterior horn were detected in cases of amyotrophic lateral sclerosis, but not in any cases with other neurodegenerative diseases. SLI in the neostriatum were also identifiable using phosphotungstic acid-hematoxylin and Gomori trichrome staining. Ubiquitin immunoelectron microscopy demonstrated that the SLI in the neostriatum corresponded to bundles of filaments. These features of SLI in the neostriatum were quite similar to those of intracytoplasmic rod-like inclusions (RLI) in the large neurons of caudate nucleus, which were first described by Kojima and Ogawa in 1974. Our findings indicate that SLI in the neostriatum are ubiquitin-related structures whose occurrence increases by aging, and less frequently accompany several neurodegenerative diseases, and are identical to at least some RLI.

alpha-Synuclein is presynaptic nerve terminal protein and its immunoreactivity has been observed in such neurodegenerative structures as senile plaques of Alzheimer's disease or Lewy bodies of Parkinson's disease. The physiological role of alpha-synuclein is still unknown. It is speculated that alpha-synuclein may be expressed in brain tumors, especially in those showing neuronal differentiation. We examined the immunohistochemical localization of alpha-synuclein in 77 human brain tumors. alpha-Synuclein was widely distributed in the brain tumors showing neuronal differentiation. As a result, positive immunostaining for alpha-synuclein was observed in ganglioglioma, medulloblastoma, neuroblastoma, primitive neuroectodermal tumor, pineocytoma/pineoblastoma, and central neurocytoma. Compared with other neuronal markers, the positive ratio of alpha-synuclein was not as high as synaptophysin, microtubule-associated protein 2, neuron-specific enolase and tau, but it was higher than neurofilament and chromogranin A. The expression of synaptophysin was diffusely observed in the cytoplasm, cellular processes and nucleus in tumors showing neuronal differentiation; however, the expression of alpha-synuclein was predominantly observed in the cytoplasm of the tumors as well as in the cellular processes. On the other hand, non-neuronal brain tumors such as astrocytic tumors or meningiomas were totally negative for alpha-synuclein. In conclusion, the appearance of an alpha-synuclein-positive structure was not limited to neurodegenerative diseases, but could also be detected in neoplastic cells showing neuronal differentiation.

Spinal cord lesions have seldom been described in cases with progressive supranuclear palsy (PSP). We thus decided to analyze spinal cord lesions by microtubule-associated protein 2 (MAP2) immunohistochemistry in six cases of PSP, five cases of Parkinson's disease (PD) and two cases of corticobasal degeneration (CBD), all of which cause parkinsonism, while six patients without any neurological disease served as controls. In the PSP cases, the MAP2 expression in the cervical spinal cords significantly decreased in the medial division of the anterior gray horn, intermediate gray and posterior gray horn, but showed no significant change in the substantia gelatinosa and lateral division of the anterior gray horn. The thoracic and lumbar spinal cords were well preserved for MAP2 immunoreactivity. In addition, the globose type neurofibrillary tangles and glial fibrillary tangles were more conspicuous in the cervical than in the thoracic and lumbar spinal cord in PSP cases. On the other hand, the PD and CBD cases showed no significant decrease of MAP2 immunoreactivity in the spinal cords. The small neurons, which are located rather selectively in the intermediate zone of the spinal cord, are considered to be mostly present in the interneurons, and are also thought to play a role in various types of focal dystonia, such as neck dystonia. We therefore consider the distinct decrease in the MAP2-positive neuronal processes in the cervical spinal cord may partly reflect the loss of interneurons and may, thereby, possibly cause nuchal dystonia.

We have studied microtubule-associated protein 2 (MAP2) expression in anterior horn neurons in the cervical and lumbar spinal cords of 19 cases of adult-onset sporadic amyotrophic lateral sclerosis (ALS) using immunohistochemistry. Specimens from 7 patients without neurological disease served as controls. MAP2 expression decreased in the anterior gray horn of all ALS cases and in the intermediate gray of several ALS cases. Such reduction correlated with the degree of degeneration or neuronal loss in anterior horn cells and with the clinical symptoms of limb weakness. Cytopathologically, the MAP2 immunoreactivity decreased corresponding to the occurrence of individual signs of neuronal degeneration, such as chromatolytic neurons, shrunken neurons and pigmented neurons. MAP2 expression was relatively well preserved in the specimens in which spheroids are conspicuous. The findings of this study demonstrate MAP2 to be an excellent marker for the detection and quantification of anterior horn degeneration in ALS.

Skeins or skein-like inclusions (SLIs) in motor neurons detected by ubiquitin immunohistochemistry are a characteristic finding of amyotrophic lateral sclerosis (ALS). Here we report ubiquitinated SLIs in the putamen and caudate nucleus from a case of ALS with dementia. A 48-year-old Japanese man developed apathy and amimia. Mental and neurological examinations revealed severe character change, muscle atrophy and fasciculation of the distal upper extremities and the tongue, and an exaggeration of the deep tendon reflex. He subsequently showed dysphagia and dysarthria. He died at the age of 51 years, after a total clinical course of about 2.5 years. By immunohistochemistry, ubiquitin-immunoreactive intraneuronal inclusions were observed in the spinal anterior horn cells, the frontal, temporal and entorhinal cortices, dentate fascia of the hippocampus and the amygdala. In addition, ubiquitinated inclusions were also seen in the putamen and caudate nucleus, which appeared as aggregates of thread-like structures similar to SLIs in the spinal anterior horn neurons. They were not seen on hematoxylin-eosin staining, and they also did not show any argentophilia nor did they react with other antibodies, including antibody against tau protein. To our knowledge, this is the first report of the presence of SLIs in non-motor neurons. Our results thus support the notion that ALS is a multisystem disease, and not simply a disease of the motor neurons.