Summary
Neuronal alterations in two cases of Werdnig-Hoffmann disease (WH) were investigated immunocytochemically and ultrastructurally. Ballooned neurons (BNs) were found in anterior horn, Clarke's column, dorsal root ganglion and thalamus. Anti-phosphorylated neurofilament antibodies preferentially stained the peripheral perikarya and proximal neuronal processes of BNs, whereas anti-ubiquitin antibodies preferentially stained the central perikarya of BNs. Ultrastructurally, BNs showed degenerative changes ranging from a diffuse increase of neurofilaments to a centrally accentuated accumulation of mitochondria and vesicular or membranous profiles. Our studies suggest that ubiquitinated degradation products accumulate in the center of the BN's perikaryon and displace aberrantly phosphorylated neurofilaments to the periphery. BNs in WH probably reflect an intrinsic alteration in the metabolism of neurofilaments that is associated with regressive changes in the neuron and eventually neuronal death.
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Carpenter S, Karpati G, Rothman S, Watters G, Anermann F (1978) Pathological involvement of primary sensory neurons in Werdnig-Hoffmann disease. Acta Neuropathol (Berl) 42:91–97
Chou SM, Fakadej AV (1971) Ultrastructure of chromatolytic motor neurons and anterior spinal roots in a case of Werdnig-Hoffmann disease. J Neuropathol Exp Neurol 30:368–379
Cork LC, Troncoso JC, Klavano GG, Johnson ES, Sternberger LA, Sternberger NH, Price DL (1988) Neurofilamentous abnormalities in motor neurons in spontaneously occurring animal disorders. J Neuropathol Exp Neurol 47:420–431
Dickson DW, Yen SH, Suzuki K, Davis P, Garcia JH, Hirano A (1986) Ballooned neurons in select neurodegenerative diseases contain phosphorylated neurofilament epitopes. Acta Neuropathol (Berl) 71:216–223
Goldstein ME, Cooper HS, Bruce J, Carden MJ, Lee VM-Y, Schlaepfer WW (1987) Phosphorylation of neurofilament proteins and chromatolysis following transection of rat sciatic nerve. J Neurosci 7:1586–1594
Haas AL, Bright PM (1985) The immunochemical detection and quantitation of intracellular ubiquitin-protein conjugates. J Biol Chem 260:12464–12473
Hsu SM, Raine L, Fanger H (1981) A comparative study of the peroxidase-antiperoxidase method and an avidin-biotin complex method for studying polypeptide hormones with radioimmunoassay antibodies. Am J Clin Pathol 75:734–738
Ihara Y, Nukina N, Miura R, Ogawa M (1987) Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem 99:1807–1811
Iwata M (1980) Glial bundles of nerve roots in Werdnig-Hoffmann disease. Ann Neurol 8:81–82
Lee S, Park YD, Yen S-HC, Ksiezak-Reding H, Goldman JE, Dickson DW (1989) A study of infantile motor neuron disease with neurofilament and ubiquitin immunocytochemistry. Neuropediatrics 20:107–111
Lippa CF, Smith TW (1988) Chromatolytic neurons in Werdnig-Hoffmann disease contain phosphorylated neurofilaments. Acta Neuropathol 77:91–94
Manetto V, Sternberger NH, Perry G, Sternberger LA, Gambetti P (1988) Phosphorylation of neurofilaments is altered in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 47:642–653
Mansour H, Bignami A, Labkovsky B, Dahl D (1989) Neurofilament phosphorylation in neuronal perikrya following axotomy: a study of rat spinal cord with ventral and dorsal root transection. J Comp Neurol 283:481–485
Mori H, Kondo J, Ihara Y (1987) Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science 235:1641–1644
Murayama S, Ookawa Y, Mori H, Nakano I, Ihara Y, Kuzuhara S, Tomonage M (1989) Immunocytochemical and ultrastructural studies of Lewy body-like hyaline inclusions in familial amyotrophic lateral sclerosis. Acta Neuropathol 78:143–152
Murayama S, Mori H, Ihara Y, Bouldin TW, Suzuki K, Tomonaga M (1990) Immunocytochemical and ultrastructural studies of lower motor neurons in amyotrophic lateral sclerosis. Ann Neurol 27:137–148
Murayama S, Mori H, Ihara Y, Tomonaga M (1990) Immunocytochemical and ultrastructural studies of Pick's disease. Ann Neurol 27:394–405
Murayama S, Bouldin TW, Suzuki K (1990) Immunocytochemical study of primary motor area in motor neuron disease (abstract). J Neuropathol Exp Neurol 49:280
Murayama S, McIlwain DL, Suzuki K (1990) Neurofilament phosphorylation and ubiquitination in frog motoneurons after ventral root axotomy (abstract). Soc Neurosci Abstr 16:141
Nakazato Y, Sasaki A, Hirato J, Ishida Y (1987) Monoclonal antibodies which recognize phosphorylated and nonphosphorylated epitopes of neurofilament protein. Biomed Res 8:369–376
Nakazato Y, Hirato J, Ishida Y, Hoshi S, Hasegawa M, Fukuda T (1990) Swollen cortical neurons in Creutzfeldt-Jakob disease contain a phosphorylated neurofilament epitope. J Neuropathol Exp Neurol 49:197–205
Nukina N, Ihara Y (1983) Immunocytochemical study on senile plaques in Alzheimer's disease. 1. Preparation of antimicrotubule-associated proteins (MAPS) and its specificity. Proc Jpn Acad 59B:284–287
Nukina N, Ihara Y (1983) Immunocytochemical study on senile plaques in Alzheimer's disease. II. Abnormal dendrites in senile plaques as revealed by anti-microtubule-associated proteins MAPs) immunostaining. Proc Jpn Acad 59B:288–292
Price DL, Porter KR (1972) The response of ventral horn neurons to axonal transection. J Cell Biol 53:24–37
Shiurba RA, Eng LF, Sternberger NH, Sternberger LA, Ulrich H (1987) The cytoskeleton of the human cerebellar cortex: an immunohistochemical study of normal and pathological material. Brain 407:205–211
Sobue G, Hashizume Y, Yasuda T, Mukai E, Kumagai T, Mitsuma T, Trojanowski JQ (1990) Phosphorylated high molecular weight neurofilament protein in lower motor neurons in amyotrophic lateral sclerosis and other neurodegenerative diseases involving ventral horn cells. Acta Neuropathol 79:402–408
Sternberger LA, Sternberger NH (1983) Monoclonal antibodies distinguish phosphorylated and non-phosphorylated forms of neurofilament in situ. Proc Natl Acad Sci USA 80:6126–6130
Sternberger LA, Hardy PH Jr, Cuculis JJ, Meyer HG (1970) The unlabeled antibody enzyme method of immunohistochemistry. Preparation and properties of soluble antigen-antibody complex (horseradish peroxidase-anti-horseradish peroxidase) and its use in identification of spirochetes. J Histochem Cytochem 18:315–333
Towfighi J, Young RSK, Ward RM (1985) Is Werdnig-Hoffmann disease a pure lower motor neuron disorder. Acta Neuropathol (Berl) 65:270–280
Zhang H, Sternberger NH, Rubinstein LJ, Herman MM, Binder LI, Sternberger LA (1989) Abnormal processing of multiple proteins in Alzeimer's disease. Proc Natl Acad Sci USA 86:8045–8049
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Supported in part by USPHS grants NS24453, HD03110, and ES01704
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Murayama, S., Bouldin, T.W. & Suzuki, K. Immunocytochemical and ultrastructural studies of Werdnig-Hoffmann disease. Acta Neuropathol 81, 408–417 (1991). https://doi.org/10.1007/BF00293462
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DOI: https://doi.org/10.1007/BF00293462