Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant

Abstract

ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may stem from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as a cardiomyopathy phenotype, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from secondary organ involvement. Over 130 different mutational variants of transthyretin have been identified, many of them being linked to specific disease symptoms. Yet, the role of these mutations in the differential disease manifestation remains elusive. Using cryo-electron microscopy, here we structurally characterized fibrils from the heart of an ATTRv patient carrying the V122Δ mutation, predominantly associated with polyneuropathy. Our results show that these fibrils are polymorphic, presenting as both single and double filaments. Our study alludes to a structural connection contributing to phenotypic variation in ATTR amyloidosis, as polymorphism in ATTR fibrils may manifest in patients with predominantly polyneuropathic phenotypes.

ATTRv-V30M Type A amyloid fibrils from heart and nerves exhibit structural homogeneity

“…The fibril structure from the nerve has free energies per residue and per chain recorded as −0.68 kcal/mol and −62.1 kcal/mol respectively, while the nerve fibrils show values of −0.73 kcal/mol and 67.5 kcal/mol per residue and per chain, respectively (as depicted in Supplementary Figure 3a-b). This level of stability is comparable to that of previously documented ATTRv and ATTRwt fibril structures 9,10,14 .…”

“…Variations in the gate have been found in ATTR-I84S cardiac fibrils 10 and ATTRv-V30M fibrils extracted from vitreous humor 8 . ATTR fibrils with multiple protofilaments have been found in the same ATTRv-V30M vitreous humor fibrils as well as in ATTR-V122Δ cardiac fibrils 8,14 . The structures of ATTRwt fibrils and other ATTRv fibrils display a single protofilament and a closed gate, and are structurally consistent 9,[11][12][13] .…”

“…Cryo-EM analysis of cardiac fibrils extracted from primarily cardiomyopathic patients reveals a consistent structural landscape 9,13 . Conversely, cardiac fibrils extracted from primarily polyneuropathy cases, such as ATTRv-I84S 10 or ATTRv-V122Δ 14 , exhibit structural polymorphism both within and between patient sample. A multi-organ study of T60A, a mutation associated with a mixed phenotype with cardiomyopathy and polyneuropathy, shows structural homogeneity in fibrils extracted from various organs of the same patient 15 .…”

“…Structural insights into amyloid fibrils have been instrumental in understanding disease classification in neurodegenerative disorders 7 and may offer significant insights into the link between structure and phenotype in ATTR amyloidosis. Much of the current understanding of the atomic structure of ATTR fibrils stems from studies on ex-vivo extracts [8][9][10][11][12][13][14] . These studies reveal that all ATTR fibrils to date share a common conformation made of two transthyretin fragments, with additional local structural variations 10 and/or multiple protofilaments 8,14 that could be influenced by the location of the transthyretin mutation.…”

“…Much of the current understanding of the atomic structure of ATTR fibrils stems from studies on ex-vivo extracts [8][9][10][11][12][13][14] . These studies reveal that all ATTR fibrils to date share a common conformation made of two transthyretin fragments, with additional local structural variations 10 and/or multiple protofilaments 8,14 that could be influenced by the location of the transthyretin mutation. The local variations are mainly found in the residues Gly 57 to Gly 67 (previously defined as gate) that close, open, or block a polar cavity formed by residues Leu 58 to Ile 84 10 .…”