Biology subjects

Bassett, P. T.

Publications and source records attributed to Bassett, P. T..

4 recordsLinked to original sources

bioRxiv2026

Transthyretin amyloid fibrils adopt distinct folds in the brain

Amyloid deposition in the central nervous system is increasingly recognized in transthyretin (ATTR) amyloidosis, particularly in patients with prolonged survival following liver transplantation or disease-modifying therapies. However, the structural basis of transthyretin aggregation in the brain remains unknown. Here we determine cryo-electron microscopy (cryo-EM) structures of ex vivo brain-derived ATTR fibrils from patients carrying the ATTRv-V30M and ATTRv-V30G variants. Both fibrils adopt folds distinct from those previously reported in peripheral tissues and the vitreous humor. V30M fibrils exhibit a continuous ordered core spanning residues Pro11-Asn124, whereas V30G fibrils consist of a substantially reduced ordered core, revealing pronounced structural divergence even within the same tissue environment. Despite this diversity, comparative analyses identify conserved regions across ATTR fibrils, including a segment implicated in transthyretin aggregation and targeted for diagnostic and therapeutic development. These results provide direct evidence that local tissue context can shape amyloid fibril architecture in human disease.

biophysics↗

bioRxiv2025

Structural polymorphism of ex-vivo ALECT2 amyloid fibrils revealed by cryo-EM

ALECT2 amyloidosis is a rare systemic disease characterized by the pathological deposition of leukocyte cell-derived chemotaxin-2 (LECT2) as amyloid fibrils, primarily affecting the kidneys and liver. The molecular mechanisms underlying LECT2 aggregation remain poorly defined, hindering diagnostic and therapeutic development. Here, we present cryo-electron microscopy structures of ex-vivo ALECT2 fibrils extracted from a patients kidney. We identified three fibril polymorphs: a predominant single-protofilament morphology and two minor double-protofilament morphologies. The dominant single-protofilament morphology comprises the full-length 133-residue LECT2 protein and retains all three native disulfide bonds. Low-resolution reconstructions of double-protofilament morphologies suggest they adopt a similar fold to the single protofilament morphology, but form paired assemblies with different inter-filament interfaces. Mass spectrometry also reveals acetylation within the fibrils. These findings offer critical insights into the structural basis of ALECT2 amyloid formation and identify molecular features that could inform future diagnostic and therapeutic approaches.

biophysics↗

bioRxiv2025

Structural variability of apolipoprotein A-I amyloid fibrils across organs, mutations, and clinical presentations, revealed by cryo-EM

Hereditary apolipoprotein A-I (AapoA-I) amyloidosis is a rare systemic disease caused by the deposition of amyloid fibrils formed by apolipoprotein A-I in multiple organs, leading to severe clinical outcomes. With no available therapies or diagnostic tools, defining the structure of AApoA-I fibrils is crucial to understanding disease mechanisms and guiding intervention. Using cryo-electron microscopy, we analyzed AApoA-I fibrils from the heart, kidney, liver, and spleen of patients carrying G26R, L90P, and R173P mutations. G26R fibrils, regardless of organ, exhibited untwisted morphologies and could not be resolved structurally. Conversely, L90P and R173P fibrils displayed a compact diabolo-shaped conformation in all organs analyzed. Their high-resolution maps enabled visualization of cis-Proline 66, which may represent a potential conformational switch during fibril formation. Our findings suggest that mutation-driven polymorphism may influence organ tropism and clinical presentation. This work advances our understanding of AapoA-I fibril assembly and provides insights toward developing targeted clinical tools.

biophysics↗

bioRxiv2024

Cryo-EM reveals that cardiac IGLV6-derived AL fibrils can be polymorphic

Immunoglobulin light chain (AL) amyloidosis is a systemic disorder caused by the misfolding and aggregation of free immunoglobulin light chains (LCs) secreted by abnormal plasma cells. The resulting amyloid fibrils deposit in multiple organs, leading to progressive dysfunction and increased morbidity and mortality. Despite recent advances, the molecular determinants of LC aggregation and phenotypic variability remain poorly understood. Structural characterization of ex-vivo fibrils provides key insights into these pathogenic processes. Here, we report cryo-electron microscopy structures of cardiac AL amyloid fibrils derived from an IGLV6 light chain. The fibrils display two distinct morphologies composed of single and double protofilaments, each adopting a previously unobserved fold. Comparison with previously reported AL fibril structures reveals that while individual mutations can alter the local conformation, IGLV6-derived fibrils share conserved structural motifs that may underlie common aggregation pathways. These findings expand the disease structural landscape and highlight sequence-dependent yet structurally constrained mechanisms of LC fibril formation.

molecular biology↗