Transthyretin Synthesis Essay


Besides functioning as the plasma transporter of retinol and thyroxine, TTR (transthyretin) is a protease, cleaving apoA-I (apolipoprotein A-I) after a phenylalanine residue. In the present study, we further investigated TTR substrate specificity. By using both P-diverse libraries and a library of phosphonate inhibitors, a TTR preference for a lysine residue in P1 was determined, suggesting that TTR might have a dual specificity and that, in addition to apoA-I, other TTR substrates might exist. Previous studies revealed that TTR is involved in the homoeostasis of the nervous system, as it participates in neuropeptide maturation and enhances nerve regeneration. We investigated whether TTR proteolytic activity is involved in these functions. Both wild-type TTR and TTRprot− (proteolytically inactive TTR) had a similar effect in the expression of peptidylglycine α-amidating mono-oxygenase, the rate-limiting enzyme in neuropeptide amidation, excluding the involvement of TTR proteolytic activity in neuropeptide maturation. However, TTR was able to cleave amidated NPY (neuropeptide Y), probably contributing to the increased NPY levels reported in TTR-knockout mice. To assess the involvement of TTR proteolytic activity in axonal regeneration, neurite outgrowth of cells cultivated with wild-type TTR or TTRprot−, was measured. Cells grown with TTRprot− displayed decreased neurite length, thereby suggesting that TTR proteolytic activity is important for its function as a regeneration enhancer. By showing that TTR is able to cleave NPY and that its proteolytic activity affects axonal growth, the present study shows that TTR has natural substrates in the nervous system, establishing further its relevance in neurobiology.

Abbreviations: Aβ, amyloid β-peptide; Abz-ESFKVS-EDDnp, aminobenzoyl-Glu-Ser-Phe-Lys-Val-Ser-ethylenediamine-2,4-dinitrophenol; apoA-I, apolipoprotein A-I; CSF, cerebrospinal fluid; Cy3, indocarbocyanine; Cy5, indodicarbocyanine; DIGE, differential fluorescence gel electrophoresis; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; HDL, high-density lipoprotein; KO, knockout; MALDI, matrix-assisted laser-desorption ionization; NPY, neuropeptide Y; PAM, peptidylglycine α-amidating mono-oxygenase; PNS, peripheral nervous system; PS-SCL, positional scanning synthetic combinatorial library; RBP, retinol-binding protein; RT, reverse transcription; T4, thyroxine; TOF, time-of-flight; TTR, transthyretin; TTRprot−, proteolytically inactive TTR; wt, wild-type

  • © The Authors Journal compilation © 2009 Biochemical Society


The liver has become an increasingly interesting target for oligonucleotide therapy. Mutations of the gene encoding transthyretin (TTR), expressed in vast amounts by the liver, result in a complex degenerative disease, termed familial amyloid polyneuropathy (FAP). Misfolded variants of TTR are linked to the establishment of extracellular protein deposition in various tissues, including the heart and the peripheral nervous system. Recent progress in the chemistry and formulation of antisense (ASO) and small interfering RNA (siRNA) designed for a knockdown of TTR mRNA in the liver has allowed to address the issue of gene-specific molecular therapy in a clinical setting of FAP. The two therapeutic oligonucleotides bind to RNA in a sequence specific manner but exploit different mechanisms. Here we describe major developments that have led to the advent of therapeutic oligonucleotides for treatment of TTR-related disease. View Full-Text

Keywords: transthyretin; familial amyloid polyneuropathy; antisense oligonucleotide; small-interfering RNA; livertransthyretin; familial amyloid polyneuropathy; antisense oligonucleotide; small-interfering RNA; liver

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Niemietz, C.; Chandhok, G.; Schmidt, H. Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis. Molecules2015, 20, 17944-17975.

AMA Style

Niemietz C, Chandhok G, Schmidt H. Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis. Molecules. 2015; 20(10):17944-17975.

Chicago/Turabian Style

Niemietz, Christoph; Chandhok, Gursimran; Schmidt, Hartmut. 2015. "Therapeutic Oligonucleotides Targeting Liver Disease: TTR Amyloidosis." Molecules 20, no. 10: 17944-17975.

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