Worm Breeder's Gazette 13(2): 61 (February 1, 1994)
These abstracts should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.
Amyloid is a general term for insoluble, fibrillar protein deposits that are associated with a number of human diseases, most prominently Alzheimer's disease. Operationally, amyloid deposits are defined by the binding of specific dyes such as Congo Red and Thioflavine S. The in vivo mechanism for the formation and apparent toxicity of amyloid deposits has not been established. As I described in the last WBG (V13, #1, pg. 66) I have been attempting to generate an amyloid disease model by expressing human amyloidic proteins in C. elegans. Using one of Andy Fire's unc-54 expression vectors, I have now established transmitting lines expressing human transthyretin (2 lines), transthyretin containing an in vitro-engineered ala60 mutation (corresponding to a mutation found in Familial Amyloid Polyneuropathy, 4 lines) and the 42 aa peptide found in ß amyloid deposits of Alzheimer's patients (4 lines). All of these lines express the appropriate proteins as assayed by immunohistochemistry (2 of the ala60 strains have not yet been tested). I have now demonstrated that all of the ß1-42 expressing lines contain Thioflavine S-binding deposits in their muscles. These deposits are not observed in controls or any of the transthyretin-expressing strains.
Unlike the transthyretin-expressing strains, a variable fraction of the ß1-42 transgenic animals show a progressive paralysis. This phenotype is most obvious in strain CL1019 ,where approximately 1/3 of the transgenic (i.e., Roller) animals become paralyzed, Egl adults. Two independent integrated lines have been generated from CL1019 by gamma irradiation; in these lines all of the animals show this phenotype (and have Thioflavine S-binding deposits).
From the results described above, I am tempted to conclude that transgenic ß1-42 expression causes the formation of toxic amyloid deposits that lead to a specific phenotype in C. elegans. However, I have not yet demonstrated that the Thio S deposits are composed of the ß1-42 peptide, nor have I quantified the gene dosage or expression levels in the various transgenic lines. It is therefore still difficult to exclude the possibility that the phenotypes observed result from non-specific, over-expression-of-foreign-protein-type effects.