Br J Ophthalmol: first published as 10.1136/bjo.60.8.547 on 1 August 1976. Downloaded from Brit. 7. Ophthal. (1976) 60, 547

Editorial: and the eye

Since the earliest days of histology, it has been and , and are predominantly found in the known that the have a large amount of particulate fraction of nerve homogenates. The basophilic material in the body. More recently slower transported material is mainly soluble this has been shown to be due to masses of rough (McEwen and Grafstein, I968; Kidwai and endoplasmic reticulum which are responsible for a Ochs, I969; Sj6strand, 1970). Much of the former high rate of protein synthesis of neurons. Since the and more than 6o per cent of the latter is probably earliest days of the microscopy of living cells in neurotubular protein (), and the vitro, particulate movement within these cells has are thought to play a major part in axonal transport been recognized, particularly in neurons (Nakai, (Schmitt and Samson, I968). The neurotubules I964). The last 30 years have seen the gradual have a similar structure to , and are linked to accumulation of the knowledge required to explain high-energy phosphate compounds. Myosin-like these two observations. In the last io years in proteins are also found in . It is suggested particular, the development of radioactive tracer that moving material might in part roll along the techniques has revealed much information on the neurotubules, or that the neurotubules themselves movement of protein and other substances within might move by a mechanism involving myosin- , a process termed axonal transport (Barondes, guanosine triphosphate- cross bonds I967). The eye and its central connexions have joining and breaking in a similar way to the sliding copyright. played a large part in the investigation of axonal flow filament process of skeletal muscle contraction. in the normal state, and reference will particularly Gross (1975) suggested a variation of this theory be made to this work here. based on regions of differential viscosity around A large number of substances are transported neurotubules (a microstream concept). As more along axons, including glycoproteins, mitochondria, studies are performed of the transport of individual vesicles, phospholipids, low molecular weight proteins in axons, it is becoming clear that there are substances, and possibly and other bio- many relatively specific rates of flow, and that the

drugs http://bjo.bmj.com/ logically active substances. However, the major overal! pattern is due to the movement of many bulk of transported material is protein. Labelling different molecular species. the proteins with a radioactive precursor such as It is known that axonal transport occurs in both 4C-leucine has demonstrated movement at different large myelinated and unmyelinated fibres, although rates, some travelling rapidly at about 400 mm/day, the evidence suggests that intermediate velocities and some slowly at about i to 4 mm/day. Some are possibly slightly faster in the unmyelinated authors have tried to suggest that the slow (Weiss, fibres (Held and Young, I969; Sj6strand, I969; 1972) or the fast (Ochs, I974) are the only rates of Gross and Beidler, 1972). Growth (Bondy and on September 27, 2021 by guest. Protected flow, but it is clear from the movement of peaks of Madsen, 197I), nerve stimulation (Jasinski, Gorb- activity in pulse labelling experiments that there man, and Hara, I966; Kreutzberg and Schubert, are preferential bands or rates of movement 1973), and probably regeneration all lead to increased (Sj6strand and Karlsson, I969; Karlsson and rates and possibly amounts of axonal transport. In Sj6strand, I97 ia and b; Chou, 1970; Di Giamberar- the- rabbit eye, however, no difference of axonal dino, 1971). It appears likely from the analysis of transport was demonstrated between animals reared the overall patterns of distribution after pulse in the dark and those in the light (Karlsson and labelling that there are many intermediate rates of Sj6strand, I97Ic). In mammals, substances are axonal transport (Bradley, Murchison, and Day, transported from the eye to the lateral geniculate 1971; Karlsson and Sj6strand, 197 I a and b). body and superior corpora quadrigemina (Sjostrand The fast and, to a lesser extent, the slow rates and Karlsson, i969; Karlsson and Sj6strand, 197Ia of transport are temperature dependent (Grafstein, and b, 1972), and in birds, material travels to the Forman, and McEwen, 1972; Ochs and Smith, optic tectum (Cuenod and Schonbach, 1971). I975), and also depend on energy metabolism Material is transported not only in an orthograde (Ochs and Ranish, I 970; Ochs, 197I). The transport direction from the perikaryon to the nerve terminal, is an intrinsic feature of the , since it continues but in a retrograde direction (Kristensson and after separation from the cell body. Most of the Olsson, 1973; Bunt, Lund, and Lund, I974), ancl faster-flowing material after pulse labelling with the latter may have a specificity for the transport of leucine consists of low molecular weight substances individual substances (St6ckel, Paravicini, and Br J Ophthalmol: first published as 10.1136/bjo.60.8.547 on 1 August 1976. Downloaded from 548 British 7ournal of Ophthalmology

Thoenan, I974; Hendry, Stach, and Herrup, 1974). dorsal roots of cats with acrylamide neuropathy, Axonal transport is blocked not only by a deficiency although transport in the peripheral branches and of high-energy phosphate compounds and cold, but in triorthocresyl phosphate neuropathy were nor- also by vincristine and which de- mal. Bird, Shuttleworth, Koestner, and Reinglass polymerize neurotubules (Karlsson and Sj6strand, (I97 I) reported impairment of slow axonal transport I969; James, Bray, Morgan, and Austin, 1970; in mice with an inherited anterior horn cell de- Sj6strand, Frizell, and Hasselgren, I970), by heavy generation (the wobbler). However, Bradley and water which stabilizes neurotubules (Anderson, Williams (I973) found only minor changes of rate Edstr6m, and Hanson, 1972), probably by cyto- and amount of both slow and fast axonal transport chalasin B which depolymerizes of protein in acrylamide, triorthocresyl phosphate, (Crooks and McClure, 1972; Fernandez and and vincristine neuropathies and concluded that Samson, 1973; McGregor, Komiya, Kidman, and they were not sufficient to explain the neural Austin, I973), and by high concentrations of local degeneration. James and Austin (1970) found no anaesthetics (Fink, Kennedy, Hendrickson, and abnormality of axonal transport in difluorophos- Middaugh, I972), but not by general anaesthetics phonate neuropathy. Bradley and Jaros (I973) found (Fink and Kennedy, 1972). no significant abnormality of fast or slow transport The function of axonal transport is still debated. of protein in wobbler mice. However, they found Jakoubek (1974) produced calculations which an increase in fast and a decrease in slow transport indicated that the amount of protein transported of protein in murine muscular dystrophy where was approximately that required to replace axolem- there are abnormalities of the spinal nerve roots mal and axonal proteins. Thus axonal transport (Bradley and Jenkison, I973). This finding was might be thought to be simply the process required extended by Komiya and Austin (I974) who found to replace the normal turnover of structural and a decrease in the 'super fast' (2000 mm/day) and of the the of an increase in the fast rate of protein transport, other proteins cell, phenomenon copyright. transport being particularly well seen because of while Tang, Komiya, and Austin (I974) found an the unusual geometry of the . In addition it increased rate of the fast transport of cholesterol is worth remembering that by virtue of its elon- and phospholipids in the sciatic nerve of dystrophic gated shape, the neuron has a very high surface-to- mice. Jablecki and Brimijoin (1974) showed that volume ratio, and thus has an unusually high there was a decreased rate of the transport of axolemmal protein turnover. Several studies have dopamine-3-hydroxylase in dystrophic mouse sciatic shown that material moving by axonal transport nerve, this enzyme being transported according to becomes incorporated into axolemmal and synaptic their results at slow rates. http://bjo.bmj.com/ membranes including synaptic vesicles (Droz, 1973; Mendell, Saida, Weiss, and Savage (1976) have Koenig, Di Giamberardino, and Bennett, I973; recently reported a decrease in the fast rates of Giorgi, Karlsson, Sj6strand, and Field, I973; transport of protein in methyl n-butyl ketone Marko and Cuenod, 1973; Krygier-Brevart, Weiss, neuropathy, which is associated with marked axonal Mehl, Schubert, and Kreutzberg, I974; Droz, swelling from neurofibrillary accumulation. It seems Rambourg, and Koenig, 1975). The role that axonal likely that in all cases with axonal swellings, in- transport plays directly in synaptic function is not cluding neuraxonal dystrophy, a significant abnor- certain. Blockage of axoplasmic flow causes some of mality of axonal transport is to be expected. on September 27, 2021 by guest. Protected the features of postsynaptic denervation of skeletal There are very few studies of axonal transport in muscle (Albuquerque,Warwick, Tasse, and Sansone, diseases of the eye. Grafstein, Murray, and Ingoglia 1972). There are several reports of material passing (1972) studied mice with hereditary degeneration across the synaptic gap to become incorporated into of the visual receptor cells, in which there is a 20 the trans-synaptic cell ((;rafstein, 1971; Alvarez per cent reduction in the number of retinal ganglion and Piischel, 1972; Korr and Appeltauer, 1974; cells. The amount of material transported at both Appeltauer and Korr, 1975), although the amount fast and slow rates was reduced by about a half, is relatively small and its functional role un- and the rate of movement of slower transport of certain. material was reduced by about one-third. Because In a number of neural diseases the distal parts of the eye has been relatively neglected for the the axons suffer the earliest and major degeneration investigation of the part that axonal transport may (dying back neuropathies) (Cavanagh, I964). It play in disease, the paper by McLeod (see page 551) seems likely that impairment of axonal transport is particularly welcome. He mentions that in the may be the basis of this distal degeneration. To experimental situation he has found localized date the results of studies of axonal transport in opaque swellings of the retinal ganglion nerve axonal neuropathies are conflicting, and their fibres at the edge of infarcts, due to the accumulation significance uncertain. Pleasure, Mishler, and Engel of mitochondria, and has gone on to demonstrate (I969) reported absent slow axonal transport in the similar opaque nerve fibre swellings in human Br J Ophthalmol: first published as 10.1136/bjo.60.8.547 on 1 August 1976. Downloaded from Editorial 549

retinal infarcts where part of the retina remains Although studies of axonal transport are virtually viable. The opaque axons are situated at the edge of impossible to undertake in man, further studies of the infarcts, and the accumulation of axoplasm is axonal transport in degenerative diseases of the essentially similar to that seen above a ligature. retina in animals are awaited with interest.

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JAMES, K. A. C., and AUSTIN, L. (1970) Brain Res., I8, 192 on September 27, 2021 by guest. Protected , BRAY, J. J., MORGAN, I. G., and AUSTIN, L. (I970) Biochem. Y., 117, 767 JASINSKI, A., GORBMAN, A., and HARA, T. J. (I966) Science, 154, 776 KARLSSON, j.-o., and SJOSTRAND, J. (I969) Brain Res., 13, 6I7 , and (I97Ia) Y. Neurochem., I8, 749 , and (I97ib) Acta neuropath., suppI. V, 207 , and (I97Ic) Brain Res., 29, 315 , and (1972) Ibid., 47, i85 KIDWAI, A. M., and OCHS, S. (I969) Y. Neurochem., I6, 1105 KOENIG, H. L., DI GIAMBERARDINO, L., and BENNETT, G. (1973) Brain Res., 62, 413 KOMIYA, Y., and AUSTIN, L. (1974) Exp. Neurol., 43, I KORR, I. M., and APPELTAUER, G. S. L. (1974) Ibid., 43, 452 KREUTZBERG, G. w., and SCHUBERT, P. (1973) In 'Central Nervous System-Studies on Metabolic Regulation and Function', eds E. Genazzani and H. Herken, p. 85. Springer-Verlag, Berlin KRISTENSSON, K., and OLSSON, Y. (1973) Progr. Neurobiol., I, 85 KRYGIER-BREVART, V., WEISS, D. G., MEHL, E., SCHUBERT, P., and KREUTZBERG, G. W. (I974) Brain Res., 77, 97 MCEWEN, B. S., and GRAFSTEIN, B. (I968) 5. Cell Biol., 38, 494 MCGREGOR, A. M., KOMIYA, Y., KIDMAN, A. D., and AUSTIN, L. (1973) 5. Neurochem., 21, 1059 MCLEOD, D. (1976) Brit. 5. Ophthal., 6o, 55I MARKO, P., and CUENOD, M. (1973) Brain Res., 6z, 419 MENDELL, J. R., SAIDA, K., WEISS, H. S., and SAVAGE, R. (1976) Neurology (Minneap.), 26, 349 NAKAI, j. (I964) In 'Primitive Motile Systems in Cell Biology', ed. R. D. Allen, and N. Kamiya, p. 377. Academic Press, New York Br J Ophthalmol: first published as 10.1136/bjo.60.8.547 on 1 August 1976. Downloaded from S50 British Journal of Ophthalmology

OCHS, S. (I971) Proc. nat. Acad. Sci. (Wash.), 68, 1279 (I974) Ann. N.Y. Acad. Sci., 228, 202 , and RANISH, N. (1970) Science, I67, 878 , and SMITH, C. (I975) Y. Neurobiol., 6, 85 PLEASURE, D. E., MISHLER, K. C., and ENGEL, W. K. (I969) Science, I66, 524 SCHMITT, F. O., and SAMSON, F. E. (eds) (I968) Neurosci. Res. Prog. Bull., 6, 113 SJOSTRAND, J. (I969) Exp. Brain Res., 8, 105 (1970) Brain Res., I8, 46I , and KARLSSON, J.-O. (1969) J. Neurochem., x6, 833 , FRIZELL, M., and HASSELGREN, P. O. (1970) Ibid., 17, 1563 STOCKEL, K., PARAVICINI, V., and THOENAN, H. (1974) Brain Res., 76, 4I3 TANG, B. Y., KOMIYA, Y., and AUSTIN, L. (1974) Exp. Neurol., 43, 13 WEISS, P. A. (1972) Proc. nat. Acad. Sci. (Wash.), 69, 1309 copyright. http://bjo.bmj.com/ on September 27, 2021 by guest. Protected