Hirano Bodies

Hirano Bodies

updated 13/5/02

Hirano bodies were first described in 1965 (Hirano, 1965). They are intracellular, paracrystalline, eosinophilic structures often occurring as rod shapes in the neurons of individuals with a number of neuro-degenerative diseases including Alzheimer's and some forms of Creutzfeldt-Jacob disease (Cartier et al, 1985). Although Hirano bodies are most often encountered in neurons of the central nervous system, particularly the Somer's section in Alzheimer's, they have been reported in glial cells, in peripheral nerve axons (Laas & Hagel, 1994), and in extraocular muscles of eyes (Tomonaga, 1983), and rarley even in skeletal muscle (Fernadez et al, 1999). Hirano bodies are observed increasingly as a function of age without obvious underlying neurodegeration (Ogata et al, 1972; Gibson & Tomlinson, 1977).

Figure 1

From Maciver & Harrington, 1995. Hirano Bodies in the CA1 area of hippocampal formation in Alzheimer's disease labelled with anti-ADF serum. Hirano bodies are restricted to this area and are found in the vicinity of pyramidal cells which are often affected by cytoplasmic granulovacoular degeneration (CGD) (A, arrows). GVD can be seen as several haemotoxalin-stained granules, each surrounded by a negatively stained halo (also seen at higher magnification in B and C). GVD was not stained with anti-ADF. The shapes of the Hirano bodies vary from small ovoid structures to longer , narrow bodies (5-10mm in width; 10-30mm in length). The majority are stained evenly throughout (A, B) although there are often bodies in which the labelling does not appear to penetrate the body, giving an appearance of the antibody reacting with epitopes on the surface of the Hirano body (arrowhead, A). Two distinct staining patterns are seen in C: one body on the left is surface labelled, whereas that on the right is labelled intensely throughout. Scale bars: A, 40mm; B,C, 10mm.

Protein	Function	References
a-actinin	An actin-filament bundling protein	Galloway et al, 1987a
actin	A structural component of almost all eukaryotic cells	Goldman 1983; Galloway et al, 1987a
ADF/cofilin	Actin-binding severing proteins.	Maciver & Harrington, 1995
b-APP (C-terminal)	The principle component of Alzheimer's tangles	Munoz et al, 1993
FAC1	Normally a nucealar protein	Jordan-Sciutto et al, 1998
HCNP	A brain signalling molecule	Mitake et al, 1995
Hsp27	A chaperonin that also binds actin	Renkawek et al, 1994
iNOS	Inducible nitric oxide synthase, a signal generating enzyme involved in smooth muscle contraction	Lee et al, 1999
MAP1	Microtubule-associated/bundling protein	Peterson et al, 1988
MAP2	Microtubule-associated/bundling protein	Peterson et al, 1988
Neurofilament proteins	An intermediate filament protein	Schmidt et al, 1989
Tau	Microtubule-associated/bundling protein	Galloway et al, 1987b
Tropomyosin	An actin binding protein that regulates interactions with myosin.	Galloway et al, 1987a; Peterson et al, 1988
Vinculin	A component of the focal adhesion complex that also binds actin.	Galloway et al, 1987a

Table 1 Proteins constituents of Hirano bodies

Actin in Hirano bodies
Actin was discovered to be a component of Hirano bodies about 20 years after their discovery (Goldman, 1983; Galloway et al, 1987a). The nature of the actin in Hirano bodies is generally supposed to be filamentous, perhaps explaining the filaments seen in regular arrays within the bodies, as Hirano bodies stain with phalloidin (a specific stain for F-actin) (Galloway et al, 1987a). More recently (Rossiter et al, 2000) it has been reported that a proportion of the actin in Hirano bodies at least exists as a fragmented form called "fractin" after it has been attacked by the apoptosis protease caspase which cleaves actin at to form two peptides and revealing a peptide (YELPD) against which antibodies were made. Hirano bodies are different from many other actin structures in that they bind both ADF/cofilin and phalloidin, normally mutually exclusive actin-binding agents.

Figure 2

The Structure of Hirano bodies
Depending on the section at the E.M. level, Hirano bodies appear to be sets of parallel filaments with equally distanced nodes or associated with feathery projections (Schochet & McCormick, 1972 ; Izumiyama et al, 1991). A representation of the simplest interpretation of the structure is given in figure 2 although it it recognised that this is very much oversimplified. This basic unit is repeated within the Hirano body. At the level of the light microscope, the structures seem to be dense as antibody complexes seem incapable of penetrating the structures fully (Maciver & Harrington, 1995; Jordan-Sciutto et al, 1998)

Lewy Bodies
Superficially at least Hirano bodies are similar to Lewy bodies. One difference is that Lewy bodies contain ubiquitin whereas Hirano bodies do not (Maciver & Harrington, 1995).

References:-

Cartier, L, Galvez, S. & Gajdusek, D.C. (1985) Familial clustering of the ataxic form of Creutzfeldt-Jacob disease with Hirano bodies. J.Neurol.Neurosurg.Psychiatry 48(3), 234-238.

Fernandez, R., Fernandez, J. M., Cervera, C., Teijeira, S., Teijeira, A., Dominquez, C. & Navarro, C. (1999) Adult glycogenosis II with paracrystalline mitochondrial inclusions and Hirano bodies in skeletal muscle. Neuromuscular Disorders. 9, 136-143.

Galloway, P. G., Perry, G. & Gambetti, P. (1987a) Hirano body filaments contain actin and actin-associated proteins. J.Neuropathol.Exp.Neurol. 46, 185-199.

Galloawy, P.G., Perry, G., Kosik, K.S., & Gambetti, P.(1987b) Hirano bodies contain tau protein. Brain Res. 403, 337-340.

Gibson, P. H. & Tomlinson, B. E. (1977) Numbers of Hirano bodies in the hippocampus of normal and demented people with Alzheimer's disease. J.Neurol.Sci. 33, 199-206.

Goldman, J.E. (1983) The association of actin with Hirano bodies. J.Neuropathol.Exp.Neurol. 42, 146-152.

Hirano, A. (1965) Pathology of amyotrophic lateral sclerosis. In: Slow latent and temperate virus infections, NINDB monograph No.2 pp23-37. Gajdosek & Gibbs eds. Bethesda. National Inst.Health.

Hirano, A. (1994) Hirano bodies and related neuronal inclusions. Neuropath.Appl.Neurobiol. 20, 3-11.

Izumiyama, N., Ohtsubo, K., Tachikawa, T. & Nakamura, H. (1991) Elucidation of three-dimentional ultrastructure of Hirano bodies by the quick-frozen, deep-etch and replica method. Acta Neuropathol. 81, 248-254.

Jordan-Sciutto, K., Dragich, J., Walcott, D. Bowser, R. (1998) The presence of FAC1 protein in Hirano bodies. Neuropath.Appl.Neurobiol. 24, 359-366.

Laas, R., Hagel, C. (1994). Hirano bodies and chronic alcoholism. Neuropathol. Appl.Neurobiol. 20, 12-21.

Lee, S.C., Zhao, M.L., Hirano, A. & Dickson, D.W. (1999). Inducible nitric oxide synthase immunoreactivity in the Alzheimer disease hippocampus: association with Hirano bodies, neurofibrillary tangle, and senile plaques. J.Neuropathol.Exp.Neurol. 11, 1163-1169.

Maciver, S. K. & Harrington, C. R. (1995) Two actin-binding proteins, actin depolymerizing factor and cofilin, are associated with hirano bodies. Neuroreport. 6, 1985-1988.

Maselli, A. G., Davis, R., Furukawa, R. & Fechheimer, M. (2002) Formation of Hirano bodies in Dictyostelium and mammalian cells induces by expression of a modified form of an actin-crosslinking protein. J.Cell Sci. 115, 1939-1952.

Mitake, S., Ojika, K., Katada, E., Otsuka, Y., Matsukawa, N. & Fujimori, O. (1995) Accumulation of hippocampal cholinergic neurostimulating peptide (HCNP)-related components in Hirano bodies. Neuropath.Appl.Neurobiol. 21, 35-40.

Peterson, C., Kress, Y., Vallee, R. & Goldman, J. E. (1988) High molecular weight microtubule-associated proteins bind to actin lattices (Hirano bodies). Acta Neuropathol. 77, 168-174.

Renkawek, K., Bosman, G. J. C. & de Jong, W. W. (1994) Expression of small heat-shock protein hsp27 in reactive gliosis in Alzheimer disease and other types of demetia. Acta Neuropathol. 87, 511-519.

Rossiter, J. P., Anderson, L. L., Yang, F. & Cole, G. M. (2000) Caspase-cleaved actin (fractin) immunolabelling of Hirano bodies., Neuropathol. Appl.Neurobiol. 26, 342-346.

Schmidt, M. L., Lee, V. M.-Y. & Trojanowski, J. Q. (1989) Analysis of epitopes shared by Hirano bodies and neurofilament proteins in normal and Alzheimer's disease hippocampus. Lab.Invest. 60, 513-522.

Schochet, S. S. & McCormick, W. F. (1972) Ultrastructure of Hirano bodies. Acta Neuropathol. 21, 50-60.

Tomanaga, M. (1983) Hirano body in extraocular muscle. Acta Neuropathol. 60, 309-313.