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Crystalline Ribosomes Are Present in Brains from Senile Humans

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Crystalline Ribosomes Are Present in Brains from Senile Humans Proc. Natl. Acad. Sci. USA Vol. 77, No. 4, pp. 2260-2264, April 1980 Medical Sciences Crystalline ribosomes are present in brains from senile humans (neurodegeneration/spatial filtering/Hirano bodies/aging/endoplasmic reticulum) LAURA O'BRIEN*, KIRK SHELLEY*, JAVAD TOWFIGHIt, AND ALEXANDER MCPHERSON*t Departments of *Biochemistry and tPathology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania 17033 Communicated by Isabella L. Karle, January 24, 1980 ABSTRACT Paracrystalline inclusions known as Hirano sequential set of particles occurring at specific intervals. Some bodies characteristically appear in the hippocampal region of details of this network are shown in Fig. 2. the brains of humans exhibiting senile and presenile dementias The structural model proposed to explain the electron mi- as well as several other neurodegenerative diseases. We present the Hirano is that the evidence that the currently accepted model for those structures croscopic images yielded by bodies based on alternating filament sheets is not correct, but that paracrystalline array arises from sheets of filaments with the Hirano bodies are stacked sheets of membrane-bound ribosomal fibers of each alternating sheet running perpendicular to those particles derived from partially degraded rough endoplasmic of adjacent sheets. Thus, the continuous strands represent the reticulum or Nissl substance. Using fluorescence staining with filaments seen longitudinally whereas the electron-dense par- acridine orange and ethidium bromide, we have shown that the ticles are presumably the fibers seen in cross section. Detailed bodies contain'RNA. Spatial filtering of electron micrographs descriptions of this model can be found in refs. 8 and 10. We by Fourier techniques shows that the individual particles that contend that this model is incorrect and does not adequately make up the arrays have a characteristic shape previously re- ported for the large subunit of eukaryotic ribosomes. The storage explain the observations. of these ribosomal particles in inclusion bodies may indicate If the' inclusion bodies were composed of stacks of fibrous a quiescent state of protein synthesis in the cells. This with- sheets, then every sheet should be essentially independent of drawal of synthetic mechanisms in the hippocampus may have those above and below. In fact, a continuous strand, presumed significant consequIences in the loss of ability to consolidate to be a filament viewed longitudinally, is seldom if ever ob- short-term to long-term memory. served without the direct association of discrete electron-dense particles. Virtually all micrographs suggest that every contin- Paracrystalline inclusion bodies (see Fig. 1) known as Hirano uous line has directly attached to it a sequential set of the dis- bodies have been found in the brains of humans under various crete particles in a specific periodic manner. Furthermore, one pathological conditions; they also occur in normal individuals. would expect the filaments lying in the substrate plane to stain They become especially prevalent with advancing age and are in a manner at least similar to the filaments seen in cross section, a particularly pronounced histological feature in patients with but they do not. The filaments seen in longitudinal section senile and presenile dementia caused by, e.g., Pick's disease and should have a diameter the same as those seen in cross section Alzheimer's disease. Although found predominantly in the (i.e., the electron-dense particles); they do not. pyramidal layer of the hippocampus, they have also been noted If the structure resulted from stacks of fibrous sheets such that in other neurological tissues under conditions of general de- those above and below any individual sheet are identical though generation. In the initial reports, the observations of Hirano oriented perpendicular to the one between, then there should bodies were confined exclusively to the central nervous system. never be any preferred pairing between doublets. That is, every They were confirmed in patients with amyotrophic lateral presumed longitudinal filament should be expected to have sclerosis and parkinsonism-dementia (1), in a patient with motor electron-dense particles on either side or on both sides simul- neuron disease (2), in kuru-infected human cerebellum (3), in taneously. This, once again, is not observed. Instead we note that mice infected experimentally with scrapie (4), and in an ado- in micrographs of Hirano bodies, the electron-dense particles lescent with hepatocerebral degeneration (5). Hirano bodies never appear simultaneously on both sides of the strands, but have also been demonstrated in the peripheral nervous system are all oriented only on one side of the strands throughout the in a line of mutant hamsters with hind-leg paralysis (6) and in entire inclusion body (i.e., there is a highly polar distribution a retroperitoneal ganglioneuroblastomd from a 4-year-old child of the particles attached to the strands). (7). It has also been suggested that they are a nonspecific ac- To our knowledge there have not been published any mi- companiment to some types of neuronal degeneration and not crographs of sections parallel with the planes of the presumptive necessarily associated with any specific disease (7-9). sheets that substantiate the proposal of alternating perpendic- Hirano bodies, when sectioned and examined by electron ular fiber arrays nor have any oblique sections appeared that microscopy, exhibit an interior composed of an ordered lattice would serve as well. In normal neuronal cells impregnated with work of alternating lines and electron-dense particles demon- silver, neurofilaments show argentophilia (11); Hirano bodies strating a high degree of periodicity in three dimensions. The do not (8, 12). paracrystalline inclusions are spindle shaped and approximately We believe that Hirano bodies are ordered, crystalline arrays 10 .um long, with a diameter of roughly half that. The indi- of membrane-bound ribosomes probably originating from vidual elements that produce the latticework arrangement fragmented rough endoplasmic reticulum or Nissl substance. appear to be long distinctive fibers or strands with an associated Further, we propose that these ribosomal arrays probably represent an inactive, or storage, form for the ribosomes that of or The publication costs of this article were defrayed in part by page arises during periods or stages dormancy degeneration. charge payment. This article must therefore be hereby marked "ad- vertisement" in accordance with 18 U. S. C. §1734 solely to indicateI t From whom reprints should be requested at: Department of Bio- this fact. chemistry, University of California, Riverside, CA 92521. 2260 Medical Sciences: O'Brien et al. Proc. Natl. Acad. Sci. USA 77 (1980) 2261 postfixed in Dalton's solution and embedded in araldite. The patient was described at autopsy as an early and asymptomatic case of Pick's disease in conjunction with the presence of rod- shaped neuronal hyalin inclusions (Hirano bodies) and granu- lovacuolar degeneration of large neurons. Ultrathin sections were photographed under an RCA EMU-4 electron microscope after staining with either uranyl acetate (2% in 50% EtOH) for 45 min or lead citrate (0.4% in 0.1 M NaOH) for 2.5 min. Tilt- stage photographs of stained sections ±24' about both vertical and horizontal axes were also recorded of appropriate sections on a Phillips 400 electron microscope. For spatial filtering of electron micrographs after visual ex- amination the following procedures were used. An optical diffraction pattern using a 3-m optical bench patterned after that of Klug and Berger (15) with a helium/neon laser light source was recorded on Ortholith transparent film in order to evaluate the level of resolution, the rough orientation of the FIG. 1. (a) Electron micrograph showing a typical example of a crystal lattice, and the degree of defocusing (16). Images re- uranyl acetate- and lead citrate-stained Hirano body in the neuron corded on glass plates were transferred to Panchromatic film of a patient with Pick's disease. [Reprinted from Towfighi, J. (1972) with care to preserve to the greatest degree possible the same Acta Neuropathol. 21, 224-231 by permission of the publisher.] relative contrast levels in the micrograph. The Optronics P-1000 (X5400.) (b) A single strand with its electron-dense particles attached microdensitometer used in these studies had a resolution of 50 at periodic intervals ofabout 21.5 nm. These strands appear to be the fundamental units of the paracrystalline array. (X45,000.) (c) A series Am and appropriate magnifications were used to avoid "aliasing of these strands are seen packed closely together to produce the effects" (17). three-dimensional array. (X56,500.) (d) A view perpendicular to a The precise film area to be scanned was determined by a sheet which constitutes the true fundamental element of the para- high-speed, low-resolution pass with a raster setting of 200 Atm crystalline array. One can easily see the distribution of ribosomal made over the entire micrograph, and the cathode ray tube particles over the surface of the membrane sheet. (X44,400.) terminal cursor was used to mark boundary points. This area was statistically analyzed (18) to ensure that the populations of MATERIALS AND METHODS optical densities were well represented and not limited by the Hippocampal tissue obtained from a patient with Alzheimer's scanners' optical density
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