A shared amyloid fold in cardiac fibrils from three neuropathy-associated ATTR variants

ATTR amyloidosis results from the systemic accumulation of wild-type (ATTRwt) or mutant (ATTRv) transthyretin amyloids, leading to multi-organ dysfunction and death. The disease exhibits variable pathology and penetrance, and its relationship with the amyloid structure remains unclear. Patients carrying the neuropathy-associated variants ATTRvI84S and ATTRv-V122Δ present polymorphic ATTR fibrils, in contrast to the consistent morphology reported for most ATTR fibrils to date. Here, we aim to elucidate a potential link between neuropathic symptomatology, distinct mutations, and amyloid structural diversity, using cryo-EM. We determined the ex vivo fibril structures from the variants ATTRv-P24S, ATTRv-A25S, and ATTRv-D38A, whose patients presented variable clinical manifestations, including neuropathy. Our findings revealed that, despite differences in mutations and diverse clinical phenotypes, these variants share a common amyloid core previously identified in ATTRwt and most cardiac ATTRv. This structural consistency is significant for the development of structure-guided diagnostic tools capable of addressing the diverse spectrum of ATTR amyloidosis.