Sulfite and base for the treatment of familial amyloidotic polyneuropathy: two additive approaches to stabilize the conformation of human amyloidogenic transthyretin

• Published in: Neurogenetics Vol. 5; no. 1; pp. 61 - 67
• Main Authors: ALTLAND, Klaus, WINTER, Pia, SARAIVA, Maria Joao M, SUHR, Ole
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.02.2004; Springer Nature B.V
• Subjects: Acidosis - drug therapy; Acidosis - genetics; Acidosis - metabolism; Acidosis/drug therapy/genetics/metabolism; Alkalies - pharmacology; Amyloid Neuropathies, Familial - drug therapy; Amyloid Neuropathies, Familial - genetics; Amyloid Neuropathies, Familial - metabolism; Amyloidosis; Biological and medical sciences; Blood Protein Electrophoresis - methods; Dimerization; Genetics; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Medical sciences; Metabolic diseases; Mutation; Neurology; Other metabolic disorders; Prealbumin - chemistry; Prealbumin - genetics; Prealbumin - metabolism; Prealbumin/chemistry/genetics/metabolism; Protein Conformation; Sulfites - pharmacology; Sulfur; Human; Nervous system diseases; Treatment; Family study; Metabolic diseases; Surgical approach; Amyloidosis; Peripheral nerve disease; Polyneuropathy; Enzymopathy; Protein; Amyloid Neuropathies; Familial/drug therapy/genetics/metabolism
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-003-0160-1

Recently, we presented evidence that sulfite protects transthyretin (TTR) from normal human individuals and heterozygotes with amyloidogenic TTR mutations against the decay of tetramers into monomers. In this paper we demonstrate a stabilizing effect of sulfite on TTR tetramers from a familial amyloidotic polyneuropathy (FAP) patient homozygous for the most-common amyloidogenic TTR-V30 M mutation. We compare the conformational stability of partially sulfonated TTR from a heterozygote for normal TTR and amyloidogenic TTR-V30 M with the stability of untreated TTR from a compound heterozygote for amyloidogenic TTR-V30 M and TTR-T119 M known to have only minor or no problems of FAP. Using a combination of polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate (SDS) gradient PAGE we demonstrate that TTR dimers containing amyloidogenic TTR mutations decay into monomers at pH<7.4. Increasing the pH by some 0.2 units within physiological ranges, i.e., pH 7.0-7.4, and sulfonation of TTR were observed to have additive inhibitory effects on the transition of dimers into monomers. We conclude that mild acidifying episodes in the interstitial volume of tissues at risk for amyloidosis could contribute to the development of FAP. Early and permanent efforts to counteract acidosis by treatment with base could possibly help to delay the onset of the disease. The intake of sulfite could support these efforts.