Biology subjects

Shahmoradian, S.

Publications and source records attributed to Shahmoradian, S..

5 recordsLinked to original sources

bioRxiv2026

Large-Scale Mutagenesis Identifies Sequence Changes That Bias Tau Toward CTE-like Aggregation

Tau amyloid fibrils adopt disease-specific structures across tauopathies, yet the sequence determinants that favor one pathological fold over another remain poorly defined. Here we combine computational saturation mutagenesis and energetic profiling, in vitro aggregation, cryo-EM and cellular seeding assays to identify sequence changes that alter tau fold compatibility. Across six tauopathy fibril structures, approximately 12,000 substitutions revealed that mutational sensitivity is concentrated within interaction networks formed by amyloidogenic motifs rather than uniformly distributed across the fibril core. Comparison of Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) folds identified residues within the 335-363 region that differentially influence fold compatibility. The S341L/S352I double mutant accelerated aggregation and remodeled packing within the PAM4-containing amyloidogenic region, producing an alternative amyloid architecture in a minimal tau fragment. S341L/S352I biosensors preferentially responded to CTE-derived over Alzheimer's disease-derived seeds, while aggregates generated from recombinant S341L/S352I tau exhibited CTE-like cellular templating behavior. Although these assemblies are not established to reproduce the atomic CTE fold, the results demonstrate that targeted sequence changes can bias tau aggregation and propagation toward a CTE-compatible state. This framework provides a strategy for defining sequence-structure relationships in polymorphic amyloids and developing conformation-selective models and biosensors.

bioengineering↗

bioRxiv2026

TIR-like NADases act in bacterial immunity and the RNA vault

Across all domains of life, organisms exploit NAD+ metabolism as a central line of defense against invading pathogens. Here, we show that domain of unknown function 4062 (DUF4062) is a widespread family of TIR-like NADases that hydrolyze NAD+ to ADP-ribose and nicotinamide. In bacteria, DUF4062 homologs form a previously unrecognized antiphage defense system, which we name Swaro[z]yc, that assembles with the phage portal into a supramolecular NADase complex to induce abortive infection. In eukaryotes, DUF4062 is found in TEP1, which we demonstrate functions as an active NADase within the RNA vault, an enigmatic organelle-like structure. Single-particle cryo-electron microscopy reveals ADP-ribose bound within the shoulder of both reconstituted and human brain vaults, while cryo-electron tomography positions TEP1 along the central axis at the shoulder. Thus, TEP1, like bacterial Swaro[z]yc, functions by depleting NAD+, providing new insight into the long-standing mystery of vault function.

biochemistry↗

bioRxiv2026

Cysteines are critical determinants of spontaneous and seeded tau aggregation in cells

The frontotemporal dementia-linked S320F mutation in the microtubule-associated protein tau promotes spontaneous aggregation, yet the structural basis of its amyloidogenesis remains unclear. Using cryo-electron microscopy, we determined the structure of an S320F295-330 tau fibril composed of parallel chains stabilized by the 306VQIVYK311 amyloid motif, with S320F buried in the fibril core and a C322-C322 disulfide linking two protofilaments. Although cysteines are dispensable for fibril formation by isolated peptide fragments in vitro, tau repeat domain constructs containing both C291 and C322 generate more potent seeds in cellular assays. In contrast, the C322S mutation suppresses spontaneous aggregation of S320F tau in cells, and combined C291S and C322S mutations inhibit seeded aggregation in both wild-type and S320F contexts. Systematic alanine mutagenesis coupled with seeding by tauopathy-derived material identifies cysteine residues as critical determinants of tau seeding, comparable in importance to core amyloid motifs. Together, these findings establish cysteines as central chemical regulators of tau aggregation and propagation.

biophysics↗

bioRxiv2025

Multi-immersion Oblique Plane Microscope (miOPM): A reconfigurable platform for high-resolution Light-Sheet Fluorescence Microscopy.

Light-Sheet Fluorescence Microscopy (LSFM) enables gentle, rapid, and efficient volumetric imaging of biological specimens. Despite its potential, LSFM has fragmented into multiple variants, each narrowly optimized for specific samples or imaging regimes, limiting its broad applicability. To overcome this barrier, we introduce the multi-immersion oblique plane microscope (miOPM), an adaptable LSFM platform for high-resolution imaging ranging from subcellular dynamics to whole organisms and cleared tissues. miOPM uniquely supports seamless interchangeability of oil, water, and air objectives, and maintains diffraction limited performance across a refractive index range of 1.33 - 1.51. It is compatible with standard sample mounting, current clearing protocols and high-throughput 3D imaging. We leverage miOPM to image diverse biological specimens at multiple spatial scales. By greatly expanding the adaptability and ease of use of LSFM, miOPM is poised to democratize advanced three-dimensional imaging.

bioengineering↗

bioRxiv2021

Micrometer-resolution reconstruction and analysis of whole mouse brain vasculature by synchrotron-based phase-contrast tomographic microscopy

Nervous tissue metabolism is mainly supported by the dense thread of blood vessels which mainly provides fast supplies of oxygen and glucose. Recently, the supplying role of the brain vascular system has been examined in major neurological conditions such as the Alzheimers and Parkinsons diseases. However, to date, fast and reliable methods for the fine level microstructural extraction of whole brain vascular systems are still unavailable. We present a methodological framework suitable for reconstruction of the whole mouse brain cerebral microvasculature by X-ray tomography with the unprecedented pixel size of 0.65 m. Our measurements suggest that the resolving power of the technique is better than in many previous studies, and therefore it allows for a refinement of current measurements of blood vessel properties. Relevant insights emerged from analyses characterizing the regional morphology and topology of blood vessels. Specifically, vascular diameter and density appeared non-homogeneously distributed among the brain regions suggesting preferential sites for high-demanding metabolic requirements. Also, topological features such as the vessel branching points were non-uniformly distributed among the brain districts indicating that specific architectural schemes are required to serve the distinct functional specialization of the nervous tissue. In conclusion, here we propose a combination of experimental and computational method for efficient and fast investigations of the vascular system of entire organs with submicrometric precision.

neuroscience↗