Filamentous Inclusions Research Articles

Unusual Intracytoplasmic Inclusions in Metastatic Carcinoma: Discussion of their Possible Significance

Unusual filamentous inclusion bodies in the cytoplasm of metastatic tumor cells are described. Their presence (intermingled with zymogen granules) seems rather restricted to cells of primary or metastatic acinar cell carcinoma of the pancreas, acinic carcinoma of salivary gland (parotid gland) and Paneth cells (neoplastic or in zinc deficiency state). For the time being, the real nature of these inclusions (deranged zymogen granules?) is unclear. This case also emphasizes the value of electron microscopy in solving the problem of the occult primary tumor and avoiding the misdiagnosis of an endocrine tumor (e.g. islet cell tumor or carcinoid), or a duct cell tumor with eosinophilic granular cytoplasm or in recognizing the foci of acinar cells in a mixed variant of carcinoma of the pancreas.

Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu,Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS)

Two different lines of mice, G1 and G20, carrying a transgene for a mutant form of Cu,Zn SOD, found in a family with familial amyotrophic lateral sclerosis (FALS), develop clinical and pathological changes which are, in their late stages, strikingly similar to those in human disease. We have analyzed the distribution and characteristics of lesions in the central and peripheral nervous systems of such mice. The most affected structure was the spinal cord, followed by the medulla, pons and midbrain. The early stages of the disease were characterized by vacuolar degeneration of anterior horn neurons and their processes, while, in the late stages, the main changes consisted of neuronal loss and atrophy of the anterior horns and the deposition in these areas of multiple filamentous inclusions resembling Lewy bodies. In the late stages of the disease, the white matter of the spinal cord was also involved, particularly in the anterior and lateral columns. Posterior columns were also involved, but to a much lesser degree. The brainstem structures also showed vacuolar degeneration of several motor nuclei and of several groups neurons in the reticular formation. Anterior roots and peripheral nerves showed the classical features of Wallerian degeneration. The dorsal root ganglia, with rare exceptions, were unremarkable. The posterior roots showed mild changes in the most severely affected mice. Changes in these two affected lines were compared to changes in mice overexpressing wild type, rather than mutant human Cu,Zn SOD. These mice never developed clinical disease, although, pathologically, they developed very mild vacuolar changes in the anterior horns of the spinal cord and in motor axons. This study shows that although simple overexpression of SOD may be injurious to motor neurons, albeit very mildly, the mutant form is necessary to produce both clinical disease and severe pathological changes which, in the chronic stage of the disease, have striking similarities to human familial ALS. A dominant gain of function, therefore, is the most likely pathogenesis of tissue injury induced by mutations in Cu,Zn SOD.

The cortical neuritic pathology of Huntington's disease.

We have studied the brains of 10 patients with clinically and pathologically defined Huntington's disease and graded the degree of striatal pathology according to the Vonsattel grading system. Sections from nine cerebral cortical areas (Brodmann areas 8, 10, 24, 33, 28, 38, 7, 39, 18), the cerebellum, hypothalamus, medulla and caudate nucleus were stained with antibodies to ubiquitin and ubiquitin C-terminal hydrolase (PGP 9.5). Dystrophic neurites, immunoreactive with ubiquitin and PGP 9.5 were detected in all cortical areas, in layers 3, 5 and 6, of all brains studied. No dystrophic neurites were found in subcortical areas or cerebellum. Sections from cortical areas 8 and 24 from the two brains with the most and least ubiquitin-immunoreactive neurites were stained with antibodies to beta-amyloid precursor protein, tau, glial fibrillary acidic protein, neurofilament protein, alpha B crystallin, GABA, cholecystokinin and somatostatin. The dystrophic neurites were found to also react with beta-amyloid precursor protein. Electron microscopy showed the abnormal neurites to contain granulofilamentous material. Granular deposits with a diameter of 40-100 nm were interspersed between randomly orientated 'fuzzy' or coated, straight or slightly curved filaments measuring 10-15 nm in diameter. These structures have not been seen in control brain and differ from age-related neuritic degeneration and neurites associated with amyloid. Immunohistochemically these structures most resemble CA 2/3 neurites seen in Lewy body disease, and, ultrastructurally, the intraneuronal filamentous inclusions in motor neuron disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Rimmed basophilic vacuoles and filamentous inclusions in neuromuscular disorders

To study the incidence of rimmed basophilic vacuoles (RBV) and 15–21 nm filamentous inclusions in neuromuscular disorders, other than inclusion body myositis (IBM) and to determine the diagnostic value of RBV quantitation in the differential diagnosis of IBM, we reviewed 1600 muscle biopsies for RBV and 750 biopsies for filamentous inclusions. The number of RBV-positive fibers per 10 mm 2 — the RBV-fiber density — was determined. The incidence of RBV in non-IBM biopsies was 8.8 per 1000. Major diagnostic categories were neurogenic disorders ( n = 7) and limb girdle muscular dystrophies (LGMD) ( n = 3). In IBM ( n = 7) the RBV-fiber density ranged from 10.4 to 63.1 and was significantly higher than in neurogenic disorders (0.9 – 4.4) and LGMD (1.1 – 2.7). The highest value was found in rigid spine syndrome (205.8). Filamentous inclusions were seen in 2.7 per 1000 non-IBM biopsies, including familial oculopharyngeal muscular dystrophy with distal myopathy (OPMD-DM), rigid spine syndrome, acid maltase deficiency and amyloid neuropathy. RBV and filamentous inclusions coexisted in rigid spine syndrome and in familial OPMD-DM. RBV, as well as filamentous inclusions, has a very low incidence in non-IBM neuromuscular disorders; the RBV-fiber density may help to discriminate neurogenic disorders and LGMD from IBM.

Filamentous inclusions in nonneoplastic and neoplastic pancreas: an ultrastructural and immunogold labeling study.

Filamentous inclusions (FI) are unusual, irregularly shaped cytoplasmic inclusions, which are mostly found in acinar cell carcinomas of the pancreas and are consequently thought to be an abnormal zymogen granule type. This study describes identical inclusions in acinar, centroacinar, and small duct epithelial cells from nonneoplastic pancreas, as well as those found in tumor cells from a mixed acinar-endocrine pancreatic carcinoma. An ultrastructural and immunogold labeling demonstration indicates that these inclusions are aggregates of intermediate filaments immunoreacting with the anti-cytokeratin AE1/AE3 mixture and with V9 clone anti-vimentin monoclonal antibodies. Their pleomorphic appearance, variable immunoreactivity, and frequent association with lipid droplets and secondary lysosomes, mostly of the angulate type, led to the hypothesis that the FI undergo a degenerative remodeling pathway similar to that proposed for hepatic Mallory bodies. A survey of the literature on FI and human tumors suggests that they are a variably expressed ultrastructural feature of tumor cells originating from exocrine cell-containing tissues, namely the pancreas and gastrointestinal tract.

Characterization of the association of phospholipase C-δ with Alzheimer neurofibrillary tangles

Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in signal transduction. We have previously demonstrated that an antibody to the PLC isozyme, PLC-δ, intensely stained neurofibrillary tangles (NFT) in the brain tissue of AD patients [ Am. J. Pathol., 139 (1991) 737–742]. To clarify the crucial involvement of abnormal PLC-δ accumulation contributing to the formation of NFT, we performed light and electron microscopic immunocytochemistry. To determine PLC-δ's association with NFT, its resistance to solubilization was also studied. Anti-PLC-δ antibody marked the same NFT-bearing neurons containing τ immunoreactivity with τ more clearly on NFT filaments and PLC-δ covering it superficially at the light microscope level. The double stained preparation with anti-PLC-δ antibody and bFGF binding suggested that PLC-δ is an intracellular marker and is not retained after neuronal death. Employing immunoperoxidase and immunogold electron microscopic immunocytochemistry, we found that the antibody to PLC-δ reacts mostly with amorphous granular materials, and occasionally with some abnormal filaments within NFT. Nevertheless, PLC-δ in NFT was resistant to removal by high salt or ionic detergent, indicating it is an integral NFT component. These results indicate that antigenic determinants unique to PLC-δ are mainly present intraneuronally on the amorphous granular components of NFT as well as the abnormal filaments, suggesting PLC-δ's interactions and possible role in the formation of intraneuronal filamentous inclusions in AD.

Chondroitin sulfate proteoglycans are a common component of neuronal inclusions and astrocytic reaction in neurodegenerative diseases

Previously, we showed three differentially sulfated forms of chondroitin sulfate proteoglycans (CSPG) associated with senile plaques, astrocytes and neurofibrillary tangles in Alzheimer's disease. Here, monoclonal antibodies were used to demonstrate CSPGs in other neurodegenerative diseases. CSPGs were found associated withinclusions of Parkinson's, diffuse Lewy body, Pick's diseases, and progressive supranuclear palsy. Reacting astrocytes in each of these neurodegenrative diseases and Huntington's disease showed immunoreactivity for CSPG. CSPG distribution in a variety of neurodegenerative diseases suggests that similar mechanisms may be involved in the accumulation of proteoglycans in a number of filamentous inclusions.

New pathological findings in amyotrophic lateral sclerosis

There have been recent developments in the pathology of sporadic ALS. A new filamentous neuronal inclusion body in ALS detected by immunohistochemical localisation of the protein ubiquitin has been characterised at the light microscopic and ultrastructural level and appears specific for the disease. The molecular composition of underlying filaments remains unresolved but the quest for this is a major aim in ALS research. Despite being a progressive degenerative process which primarily affects motor systems, ALS is now recognised to involve several non-motor systems and in long survivors affects many subcortical structures. There is also accumulating evidence that the neurodegenerative process underlying ALS may present as a non-motor clinical syndrome, particularly as a frontal lobe dementia with characteristic inclusions present in the non-motor cortex. Considering ALS as a multisystem disease rather than simply a disease of motor neurones has major implications for research into pathogenesis.

Einschlußkörpermyositis

Inclusion body myositis is a distinct entity among the idiopathic inflammatory myopathies which encompass polymyositis, dermatomyositis, and inclusion body myositis. The diagnosis of inclusion body myositis requires the consistent combination of characteristic clinical findings with distinctive histopathological features. The main clinical features are insidious onset of slowly progressive muscular weakness and wasting, normal or mildly elevated CK-levels, EMG findings consistent with a myopathy, and refractoriness to corticosteroids. The histological hallmarks of the disease include vacuoles rimmed by basophilic material in numerous muscle fibres, groups of atrophic fibres, endomysial inflammatory infiltrates, and filamentous inclusions seen on electron microscopy. Current knowledge of clinical findings, histological features, pathogenesis and treatment of the disease is reviewed.

Ubiquitin and neurofilament expression in anterior horn cells in amyotrophic lateral sclerosis: possible clues to the pathogenesis.

Cytoskeletal abnormalities are a prominent pathological feature of anterior horn cells in amyotrophic lateral sclerosis (ALS), and are thought to be involved in the process of motor neuron death. Skein-like filamentous inclusions have been detected by immunocytochemical staining for ubiquitin, a stress protein involved in targeting abnormal proteins for proteolysis. So far, identification of the target protein has been elusive. We have studied the ultrastructural localization of ubiquitin and neurofilaments by post-embedding immunogold staining. In skein-like arrays, strong ubiquitin labelling was concentrated on abnormally formed 15-20 nm filaments; neurofilament labelling was localized on 10 nm filaments adjacent or in continuity with the abnormal filaments. In addition, Bunina bodies were a major site of ubiquitin accumulation. Our results suggest that ubiquitinated filaments in skein-like inclusions might originate from abnormally aggregated neurofilament proteins, which are no longer recognized by antibodies to neurofilament epitopes. Furthermore, the presence of ubiquitin in Bunina bodies suggests that, in addition to its protective role, ubiquitin might be directly implicated in the mechanism of programmed neuronal death in ALS.

Cytopathology of Mature Ovaries from Lettuce Plants Infected by Lettuce Mosaic Potyvirus

The location of lettuce mosaic potyvirus (LMV) in mature ovaries of lettuce plants (Lactuca sativa) was studied by conventional thin‐section electron microscopy and immunogold cytochemistry. Flexuous filamentous particles and inclusion bodies characteristic of LMV infection were observed in the integumentary tapetum, integument and ovary wall of the mature ovary but not in the embryo sac.

Abnormal accumulation of phospholipase C-δ in filamentous inclusions of human neurodegenerative diseases

We have previously demonstrated that an antibody to phosphoinositide-specific phospholipase C (PLC) isozyme, PLC-δ, intensely stained neurofibrillary tangles (NFT) in the brain tissue of Alzheimer's disease (AD). This study was performed to determine if abnormal PLC-δ accumulation might be present in the filamentous inclusions of other neurodegenerative diseases. We found that the anti-PLC-δ antibody stained neuronal inclusions of Pick's disease, progressive supranuclear palsy and diffuse Lewy body disease while the inclusions of idiopathic Parkinson's disease lacked PLC-δ accumulation. These results suggest a possible role for PLC-δ interaction in the formation of intraneuronal filamentous inclusions in human neurodegenerative diseases.

Comparative Light and Electron Microscopic Analyses of Tenuivirus Major Noncapsid Protein (NCP) Inclusion Bodies in Infected Plants, and of the NCP in Vitro

Tenuivirus infections are associated with the formation of abundant inclusion bodies and with the accumulation of large quantities of a viral noncapsid protein (NCP) in infected plants. Examination of maize stripe virus and rice hoja blanca virus-infected plant tissues using light, immunofluorescent, and electron microscopy showed that the inclusion bodies induced by the two viruses were very similar. Light microscopy revealed that both induced arrays of ring-like, figure-eight-like, and amorphous inclusions, frequently with a substructure of needle-shaped crystals. Immunofluorescent staining showed that all types of inclusion bodies contained the viral NCP but not the viral N protein, associated to the viral RNA. Electron microscopy revealed abundant amorphous semi-electron-opaque inclusion bodies; these had a fibrillar appearance but also occurred as compact, more electron-dense structures. Filamentous electron-opaque inclusion bodies were also detected. Immunogold labeling of ultrathin sections confirmed that all inclusion bodies included NCP and that none included viral N protein. Examination of purified NCP showed that it can form similar amorphous and crystalline arrays in vitro to the inclusion bodies observed in vivo. We propose that the common presence of NCP in all inclusion bodies implies the existence of a single type of intracellular inclusion body, the different developmental stages of which have previously been considered to be distinct inclusion bodies.

Neurofilament mRNA is reduced in Parkinson's disease substantia nigra pars compacta neurons.

Lewy bodies are filamentous neuronal inclusions characteristic of Parkinson's disease, and neurofilament triplet proteins are the major components of the filaments in Lewy bodies. Since the neurofilament proteins found in Lewy bodies are abnormally phosphorylated and partially degraded, the formation of Lewy bodies may be due to the defective metabolism of these proteins, and this could lead to impairments in the structure and function of neurofilament rich neuronal processes (i.e., large caliber axons). To gain further insights into the metabolism of neurofilaments in Parkinson's disease, we evaluated neurofilament mRNA levels by semi-quantitative in situ hybridization histochemistry in postmortem tissues from Parkinson's disease and control subjects. Substantia nigra pars compacta neurons were examined with digoxigenin-UTP labeled cRNA probes to the heavy and light neurofilament mRNAs. The relative abundance of these mRNAs was measured by videodensitometric image analysis of chromogenic reaction product. Using this approach, we demonstrated that the levels of both heavy and light neurofilament mRNAs were reduced in Parkinson's disease substantia nigra pars compacta neurons. Additionally, the levels of heavy neurofilament mRNA were lowest in Lewy body containing neurons in the Parkinson's disease cases. These results suggest that the formation of neurofilament-rich Lewy bodies in substantia nigra pars compacta neurons is associated with reduced levels of the heavy and light neurofilament mRNAs in Parkinson's disease. Thus, it is possible that the accumulation of abnormal neurofilament proteins in Lewy bodies and diminished neurofilament mRNAs contribute to the degeneration of substantia nigra pars compacta neurons in Parkinson's disease.

Alz-50 immunohistochemistry in the normal sheep striatum: a light and electron microscope study

Alz-50 is a monoclonal antibody raised against ventral forebrain tissue from patients with Alzheimer's disease (AD). It was originally believed that the antigen recognized by Alz-50 was only found in degenerating neurons. However, recent studies indicate that Alz-50 stains neurons in a limited but specific distribution in normal brains throughout life. As the antigen recognized by Alz-50 in normal brains may give some insight into the AD degenerative process, we characterized Alz-50 staining in the normal ovine striatum using immunoblots and immunocytochemistry at the light and electron microscope levels. We then compared the Alz-50 staining pattern with those of NADPH diaphorase histochemistry and immunocytochemistry using antisera against several neuropeptides. Alzheimer-related proteins, and heat-shock proteins. Western blot analysis indicated that the epitope recognized by Alz-50 in the normal sheep brain is on the microtubule-associated protein tau, and preadsorbing Alz-50 with a peptide corresponding to the amino terminus of the tau molecule eliminated staining. Alz-50 labeled a single population of cells in the ovine striatum, the medium aspiny neurons. At the light microscope level, the granular staining pattern closely resembled Alz-50 immunoreactive neurons in the normal human striatum and in cells undergoing early degeneration in AD. Alz-50 immunoreactive neurons stained immunocytochemically with antisera against somatostatin, neuropeptide Y, and histochemically for NADPH diaphorase. These cells were morphologically characterized by smooth dendrites, elaborate local axonal plexuses, and indented nuclei with filamentous inclusions. Ultrastructurally, Alz-50 immunodecorated ribosomes and membranous structures (e.g. vesicles, endoplasmic reticulum), and many boutons which contained Alz-50-positive synaptic vesicles. None of the antisera against other Alzheimer-related proteins, including paired helical filament protein, ubiquitin, β-amyloid protein, or heat-shock proteins specifically stained the population of cells labelled by Alz-50. Other tau antisera also did not specifically stain these cells. We conclude that Alz-50 recognizes an amino terminal epitope that is exposed on tau proteins within a single, discrete population of neurons in the normal sheep striatum. The presence of this epitope in a normal cell population raises the possibility that the early stages of AD degeneration may involve the activation of a normal cellular pathway that modifies the tau molecule.

Ubiquitin in Neurodegenerative Diseases

Immunochemical staining to detect ubiquitin has become an essential technique in evaluating neurodegenerative processes. Age related staining is seen in myelin, in nerve processes in lysosome-related dense bodies, and in corpora amylacea. There is a constant association between filamentous inclusions and the presence of ubiquitin. Intermediate filaments associated with ubiquitin, alpha B crystallin and enzymes of the ubiquitin pathway are the basis of Lewy bodies and Rosenthal fibres, as well as related bodies outside the nervous system. Neurofibrillary tangles in diverse diseases are associated with ubiquitin as are several other tau containing inclusions in both neurones and glia. Inclusions in motor neurones and non-motor cortex characterizing amyotrophic lateral sclerosis (ALS) and certain related forms of frontal lobe dementia can only be readily detected by anti-ubiquitin. Anti-ubiquitin also identifies both filamentous and lysosomal structures in neuronal processes as well as in some swollen neurones. Involvement of ubiquitin-containing elements of the lysosomal system appears important in pathogenesis of prion encephalopathies. Despite great advances in understanding cell biology of the ubiquitin pathway there are as yet few insights into the precise role played by ubiquitin in neuronal disease.

Muscle fibre degeneration in distal myopathy (Welander)—Ultrastructure related to immunohistochemical observations on cytoskeletal proteins and Leu-19 antigen

In seven patients with long-standing and six patients with early symptoms of Welander distal myopathy (WDM), monoclonal antibodies directed against such cytoskeletal proteins as dystrophin, spectrin and desmin and against Leu-19, a myoblast and satellite cell related antigen, were applied to muscle biopsies from the anterior tibial and soleus muscles. In addition, ultrastructural studies were carried out on biopsies from the soleus muscle. In muscle fibres from patients with early symptoms there was normal immunostaining for dystrophin, spectrin, desmin and Leu-19. In the patients with long-standing symptoms, there was also a normal expression of dystrophin, and a normal staining for spectrin and desmin was found in normal sized muscle fibres. Occasionally normal sized muscle fibres showed staining for Leu-19. Increased staining for spectrin and desmin and a strong Leu-19 staining was seen in normal sized muscle fibres with rimmed vacuoles and in atrophic fibres. Increased staining for spectrin, desmin and Leu-19 has been described in denervated muscle fibres and, thus, the present findings may support earlier findings of a neurogenic component in Welander distal myopathy. In the soleus muscle, ultrastructural muscle fibre abnormalities conformed to those in the anterior tibial muscle. Many rimmed vacuoles were observed which corresponded, at the ultrastructural level, to autophagic vacuoles. Intranuclear and cytoplasmic filamentous inclusions of the same shape and diameter as in inclusion body myositis were observed.

Inclusion body myositis: clinical and histopathological features of 36 patients.

Thirty-six patients (15 females, 21 males) with inclusion body myositis (IBM) were studied. The diagnosis was established according to clinical and histopathological criteria. Clinical features were insidious onset of slowly progressive muscle weakness and wasting with depressed or absent tendon reflexes especially in the lower limbs. The pattern of muscle weakness was variable. The majority of patients (58%) showed proximal and symmetrical weakness usually most prominent in the legs. Isolated distal (6%) and asymmetrical weakness (19%) was less frequently observed. Myalgia occurred in 42% of the patients. The age at onset of symptoms ranged from 20 to 73 years (mean 47 years). Serum creatine kinase levels were normal (11%) or mildly elevated (89%). Needle electromyography revealed myopathic features in about 80% of the patients, and results of nerve conduction studies were normal in most of the cases. The predominant histopathological findings were numerous muscle fibers with rimmed vacuoles (100% of the patients), groups of atrophic fibers (92%), and inflammatory infiltrates (89%). The inflammatory infiltrates were located predominantly at endomysial sites and were composed mainly of T8 cells. Electron microscopy showed characteristic intracytoplasmic filamentous inclusions in all 36 cases. Immunosuppressive treatment in 16 patients failed to prevent disease progression in all but one patient with an associated Sjögren's syndrome. It is concluded that the consistent combination of typical histopathological findings and characteristic clinical features offers a firm basis for the diagnosis of IBM. IBM should be suspected in any adult patient presenting with clinical signs of a chronic polymyositis unresponsive to immunosuppressive therapy. The etiology and pathogenesis of IBM remain to be established.

Basic fibroblast growth factor binds to filamentous inclusions of neurodegenerative diseases

The extracellular matrix protein heparan sulfate proteoglycans (HSPG) has been found in the neurofibrillary pathology of Alzheimer disease. This study was performed to determine if similar proteoglycans might be present in the fibrillary inclusions of other neurodegenerative disease. Basic fibroblast growth factor (bFGF) binding to heparinase sensitive sites was used as an assay for HSPGs. We found that the inclusions of Pick and Parkinson diseases as well as progressive supranuclear palsy contained heparinase sensitive bFGF binding sites while the inclusions of diffuse Lewy body disease lacked bFGF binding sites. These findings indicate that HSPG's interactions and possible role in the formation of intraneuronal inclusions are not limited to Alzheimer disease.

Alpha B crystallin expression in non-lenticular tissues and selective presence in ubiquitinated inclusion bodies in human disease.

alpha B crystallin is a lens protein which has homology with the small heat-shock proteins and is also expressed in non-lenticular tissues. Polyclonal antibodies have been raised to a synthetic peptide corresponding to residues 1-10 of alpha B crystallin. The antiserum detects a 20 kDa polypeptide on nitrocellulose replicas after polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate of extracts of heart muscle known to be rich in alpha B crystallin. Staining of normal human tissues reveals immunoreactivity of lens capsular epithelium, skeletal muscle, cardiac muscle, smooth muscle, renal tubular epithelium, Schwann cells, and glial cells, as has been described by other workers. In addition, positive staining of normal thyroid epithelium, colonic epithelium, and stratified squamous epithelium was seen. Tissues known to contain ubiquitinated inclusion bodies were immunostained with the anti-alpha B-crystallin antiserum. Staining of cortical Lewy bodies, astrocytic Rosenthal fibres, and hepatic Mallory bodies was seen, but only a proportion of inclusions were positive. Neurones containing the ubiquitinated inclusions of Alzheimer's disease were only very rarely immunostained and the ubiquitinated inclusions of motor neurone disease were not detected by the antiserum. Reactive astrocytes in cerebral tissues were strongly immunostained. The results suggest that alpha B crystallin is involved in the formation of ubiquitinated inclusion bodies that have associated intermediate filaments and support previous observations on the localization of a brain-specific ubiquitin carboxy-terminal hydrolase which similarly divides ubiquitinated filamentous inclusions in the central nervous system into two main groups.