Down regulation of a harmful variant protein by replacement of its normal protein

Abstract

To compensate for the hypoprotein and hypoalbuminemia of familial amyloidotic polyneuropathy (FAP) patients, 800 ml of fresh frozen plasma (FFP) was intravenously administered and change in total and variant transthyretin (TTR) levels were measured in the plasma. After injection of FFP, total plasma TTR levels were elevated and variant TTR levels decreased from 24 to 48 h, accompanied by an elevation of plasma total protein, albumin levels and TTR levels. To elucidate the mechanism of this phenomenon, a large amount of purified normal TTR from normal human plasma was intravenously injected in mice and FAP patients. By intravenous injection of 3 mg of the purified TTR to C57Black6, the expression of TTR mRNA decreased from 6 to 24 h post injection, and gradually increased up to 48 h post injection. After injecting 400 mg of normal TTR in each of 3 FAP patients, total plasma TTR levels were elevated and variant TTR levels decreased significantly from 24 to 48 h. These results suggested that down regulation of the harmful protein by replacement of its normal form of the protein occurred by this method. This phenomenon should be applied as the basis for one of the useful methods for decreasing the harmful proteins in the circulation.

Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy

“…15,22 Albumin was isolated from serum samples from healthy volunteers by means of ion-exchange chromatography. Albumin-containing bound fatty acids (FA-albumin) was donated by the Chemo-Sero-Therapeutic Research Institute (Kaketsuken, Kumamoto, Japan) and was isolated by using a Sephadex G-25 column (Nihon Waters K.K., Tokyo, Japan).…”

Transthyretin forms amyloid fibrils at physiological pH with ultrasonication

“…Purification of WT-TTR from human plasma WT-TTR was purified from serum samples obtained from healthy volunteers, as described previously [8].…”

SELDI-TOF Mass Spectrometry Evaluation of Variant Transthyretins for Diagnosis and Pathogenesis of Familial Amyloidotic Polyneuropathy

“…2). ATTR V30M was also identified in CSF and aqueous humor (see online Supplemental We attempted to correlate the ratio of the intensity derived from ATTR V30M and mixed samples of ATTR V30M and WT TTR that were purified from serum specimens obtained from a healthy volunteer and a patient homozygous for FAP ATTR V30M, respectively, as described previously (14 ). Ratios obtained showed good correlation with ATTR V30M/WT TTR (see online Supplemental Fig.…”