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Journal of Neuroscience, Vol 14, 538-544, Copyright © 1994 by Society for Neuroscience
Toxicity of an antitumor ribonuclease to Purkinje neurons
DL Newton, S Walbridge, SM Mikulski, W Ardelt, K Shogen, SJ Ackerman, SM Rybak and RJ Youle
Biochemistry Section, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Purkinje cell toxicity is one of the characteristic features of the Gordon
phenomenon, a syndrome manifested by ataxia, muscular rigidity, paralysis,
and tremor that may lead to death (Gordon, 1933). Two members of the RNase
superfamily found in humans, EDN (eosinophil- derived neurotoxin) and ECP
(eosinophil cationic protein), cause the Gordon phenomenon when injected
intraventricularly into guinea pigs or rabbits. We have found that another
member of the RNase superfamily, an antitumor protein called onconase,
isolated from Rana pipiens oocytes and early embryos, will also cause the
Gordon phenomenon when injected into the cerebrospinal fluid of guinea pigs
at a dose similar to that of EDN (LD50, 3-4 micrograms). Neurologic
abnormalities of onconase- treated animals were indistinguishable from
those of EDN-treated animals, and histology showed dramatic Purkinje cell
loss in the brains of onconase-treated animals. The neurotoxic activity of
onconase correlates with ribonuclease activity. Onconase modified by
iodoacetic acid to eliminate 70% and 98% of the ribonuclease activity of
the native enzyme displays a similar decrease in ability to cause the
Gordon phenomenon. In contrast, the homologous bovine pancreatic RNase A
injected intraventricularly at a dose 5000 times greater than the LD50 dose
of EDN or onconase is not toxic and does not cause the Gordon phenomenon. A
comparison of the RNase activities of EDN, onconase, and bovine pancreatic
RNase A using three pancreatic RNA substrates demonstrates that onconase is
orders of magnitude less active enzymatically than EDN and RNase A. Thus,
another member of the RNase superfamily in addition to EDN and ECP can
cause the Gordon phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)
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