PubMed · 6585571
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J Varga. 1984. Amyloidosis.. https://pubmed.ncbi.nlm.nih.gov/6585571/
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Familial amyloidotic polyneuropathies are autosomal-dominant, inherited disorders that are characterised by the aggregation of variant proteins in a fibrillar form and by the extracellular deposition of amyloid fibrils. In familial amyloidotic polyneuropathy type I the protein constituent is a variant transthyretin molecule that has a Val to Met substitution at residue 30. Patients with this form of the disease present with sensory and motor disturbances, widespread autonomic dysfunction and in some cases, vitreous opacities. We have used amyloid material from the vitreous humours of patients homozygous for this mutation and analysed the structure of the fibrils by thin section electron microscopy and image reconstruction. Cross-sectional images of 200 different fibrils were collected and aligned, manually at first and then with an automated process that uses iterative cross-correlation. The averaged cross-section calculated produced a detailed view of the fibril substructure. The diameter of the fibrils is about 130 A. In cross-section they exhibit 4-fold symmetry with four proto-filaments, each measuring 40 to 50 A across, arranged around a central hollow core.
By serially measuring blood flow and venous-arterial lactate differences across the hindlimb of the fasted anesthetized rat, we examined (1) whether exogenous amylin increased muscle lactate production in vivo, (2) whether glucose administration increased muscle lactate production, and (3), by using the selective amylin antagonist AC187 to block endogenous peptide, whether amylin secreted in response to glucose could mediate muscle lactate production. Abdominal aortic flow was unchanged by any treatment. Hindlimb lactate production was increased by both 100 micrograms s.c. amylin (4.0 +/- 0.4 cf 2.6 +/- 0.3 mumol/min after saline, P < 0.05) and by infusion of 2mmol D-glucose (3.0 +/- 0.2 cf 2.3 +/- 0.2 mumole/hr after saline, P < 0.03). The increase in hindlimb lactate production was prevented by infusion of AC187 (mean post-treatment venoarterial delta-lactate 140 +/- 11 microM; n.s. vs saline-treated delta-lactate 154 +/- 10 microM; P < 0.05 vs glucose-treated delta-lactate 201 +/- 14 microM). These findings are consistent with endogenous amylin secreted in response to a glucose challenge having acted at skeletal muscle to release lactate.
In order to determine whether distributing the pairing bases in helices I and III of a hammerhead ribozyme asymmetrically would enhance the cleavage of trans-acting ribozymes designed to degrade cellular mRNAs, we measured the cleavage properties of symmetric and asymmetric ribozymes targeted to the amyloid peptide precursor (beta APP) mRNA. Five ribozymes were formed from three beta APP synthetic mRNA analogs and two ribozyme RNA core sequences. Symmetric ribozymes beta 133/Rz133 and beta 125/Rz133 contained 8 bp in helix I and 7 bp in helix III. Asymmetric ribozyme beta 125/Rz125 had 13 bp in helix I and 4 bp in helix III, asymmetric ribozyme beta 123/Rz125 had 11 bp in helix I and 4 bp in helix III, while asymmetric ribozyme beta 133/Rz125 contained 8 bp in helix I and 4 bp in helix III. The ability of each ribozyme to cleave its substrate RNA was first assessed under single-turnover conditions at 37 degrees C. These studies revealed that only symmetric ribozyme, beta 133/Rz133, and asymmetric ribozyme beta 123/Rz125 effectively cleaved their substrates. Further studies using a 80 degrees C, 1-min-->37 degrees C, 1-min temperature cycling paradigm were performed to increase the cleavage efficiency of the ribozymes. Under these conditions ribozymes beta 133/Rz133, beta 125/Rz125, and beta 123/Rz125 were kinetically well behaved. Therefore, the fact that the symmetric ribozyme beta 133/Rz133 was more active than its asymmetric counterparts indicates that symmetrically distributing the pairing bases in helices I and III around this cleavage site is preferred.