Tagliavini F, Prelli F, Verga L, Giaccone G, Sarma R, Gorevic P, Ghetti B, Passerini F, Ghibaudi E, Forloni G
Istituto Nazionale Neurologico Carlo Besta, Milan, Italy.
Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9678-82. doi: 10.1073/pnas.90.20.9678.
Gerstmann-Sträussler-Scheinker disease (GSS) is a prion-related encephalopathy pathologically characterized by massive deposition of prion protein (PrP) amyloid in the central nervous system. The major component of amyloid fibrils isolated from patients of the Indiana kindred of GSS (GSS-Ik) is an 11-kDa fragment of PrP spanning residues 58 to approximately 150. These patients carry a missense mutation of the PRNP gene, causing a Phe-->Ser substitution at codon 198. We investigated fibrillogenesis in vitro by using synthetic peptides homologous to consecutive segments of GSS-Ik amyloid protein (residues 57-64, 89-106, 106-126, and 127-147) as well as peptides from the PrP region with the GSS-Ik mutation (residues 191-205 and 181-205, both wild type and mutant). Peptide PrP-(106-126) formed straight fibrils similar to those extracted from GSS brains, whereas peptide PrP-(127-147) formed twisted fibrils resembling scrapie-associated fibrils isolated from subjects with transmissible spongiform encephalopathies. Congo red staining and x-ray fibril diffraction showed that both straight and twisted fibrils had tinctorial and conformational properties of native amyloid. Conversely, the other peptides did not form amyloid-like fibrils under similar conditions. These findings suggest that the sequence spanning residues 106-147 of PrP is central to amyloid fibril formation in GSS and related encephalopathies.
格斯特曼-施特劳斯勒-谢inker病（GSS）是一种与朊病毒相关的脑病，其病理特征是朊病毒蛋白（PrP）淀粉样蛋白在中枢神经系统中大量沉积。从GSS印第安人家族（GSS-Ik）患者中分离出的淀粉样纤维的主要成分是PrP的一个11 kDa片段，其跨度为58至约150位氨基酸残基。这些患者携带PRNP基因的错义突变，导致第198密码子处的苯丙氨酸（Phe）被丝氨酸（Ser）取代。我们通过使用与GSS-Ik淀粉样蛋白连续片段同源的合成肽（57-64位氨基酸残基、89-106位氨基酸残基、106-126位氨基酸残基和127-147位氨基酸残基）以及来自具有GSS-Ik突变的PrP区域的肽（191-205位氨基酸残基和181-205位氨基酸残基，包括野生型和突变型）来研究体外纤维形成。肽PrP-(106-126)形成了与从GSS脑提取物中相似的直纤维，而肽PrP-(127-147)形成了类似于从患有传染性海绵状脑病的受试者中分离出的羊瘙痒病相关纤维的扭曲纤维。刚果红染色和X射线纤维衍射表明，直纤维和扭曲纤维都具有天然淀粉样蛋白的染色和构象特性。相反，其他肽在类似条件下未形成淀粉样纤维。这些发现表明，PrP的106-147位氨基酸残基序列对于GSS和相关脑病中淀粉样纤维的形成至关重要。
