Biology subjects

Pan, H. S.

Publications and source records attributed to Pan, H. S..

3 recordsLinked to original sources

bioRxiv2026

Distinct tau filament folds in familial frontotemporal dementia due to the MAPT S305I mutation

Frontotemporal lobar degeneration with tau inclusions (FTLD-tau) comprise a class of fatal heterogeneous neurodegenerative diseases. Approximately 10% arise from pathogenic MAPT mutations and often cause severe, early-onset disease with pathology that is distinct yet partially overlapping with sporadic cases. Here, we evaluated post-mortem tissue from a patient with FTLD-tau due to MAPT S305I showing neuropathology most consistent with argyrophilic grain disease (AGD), a prevalent limbic tauopathy of aging. Structures determined by cryo-electron microscopy reveal tau filament folds that differ from those found in sporadic AGD or other tauopathies and feature a 4-layer architecture stabilized by the Ile substitution within its core. Comparative structural analysis reveals conserved motifs are shared among AGD, corticobasal degeneration, and MAPT P301T. A well-defined density stacks along a cationic cleft, indicative of a bound RNA-like polyanion or small-molecule. In vitro analysis shows the S305I mutation promotes fibrilization relative to normal tau. These results demonstrate that MAPT S305I stabilizes a distinct aggregation-prone tau fold that likely contributes to disease pathology and heterogeneity beyond its known splicing defects, and underscore potential limitations of using the most pathologically similar genetic form as a model for sporadic FTLD-tau.

neuroscience↗

bioRxiv2021

Cross-seeding Controls Aβ Fibril Populations and Resulting Function

Amyloid peptides nucleate from monomers to aggregate into fibrils through primary nucleation; pre-existing fibrils can then act as seeds for additional monomers to fibrillize through secondary nucleation. Both nucleation processes can occur simultaneously, yielding a distribution of fibril polymorphs that can generate a spectrum of neurodegenerative effects. Understanding the mechanisms driving polymorph structural distribution during both nucleation processes is important for uncovering fibril structure-function relationships, as well creating polymorph distributions in vitro that better match distributions found in vivo. Here, we explore how cross-seeding WT A{beta}1-40 with A{beta}1-40 mutants E22G (Arctic) and E22{Delta} (Osaka), as well as with WT A{beta}1-42 affects the distribution of fibril structural polymorphs, and how changes in structural distribution impact toxicity. Transmission electron microscopy analysis reveals that fibril seeds derived from mutants of A{beta}1-40 impart their structure to WT A{beta}1-40 monomer during secondary nucleation, but WT A{beta}1-40 fibril seeds do not affect the structure of fibrils assembled from mutant A{beta}1-40 monomers, despite kinetics data indicating accelerated aggregation when cross-seeding of any combination of mutants. Additionally, WT A{beta}1-40 fibrils seeded with mutant fibrils to produce similar structural distributions to the mutant seeds also produced similar cytotoxicity on neuroblastoma cell lines. This indicates that mutant fibril seeds not only impart their structure to growing WT A{beta}1-40 aggregates, but they also impart cytotoxic properties. Our findings provide clear evidence that there is a relationship between fibril structure and phenotype on a polymorph population level, and that these properties can be passed on through secondary nucleation of succeeding generations of fibrils.

biochemistry↗

bioRxiv2020

Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

The aggregation of Amyloid-{beta} (A{beta}) is associated with the onset of Alzheimers Disease (AD) and involves a complex kinetic pathway as monomers self-assemble into fibrils. A central feature of amyloid fibrils is the existence of multiple structural polymorphs, which complicates the development of disease-relevant structure-function relationships. Developing these relationships requires new methods to control fibril structure. In this work, we demonstrate that mesoporous silicas (SBA-15) functionalized with hydrophobic (SBA-PFDTS) and hydrophilic groups (SBA-PEG) direct the aggregation kinetics and resulting structure of A{beta}1-40 fibrils. The hydrophilic SBA-PEG had little effect on amyloid kinetics while as-synthesized and hydrophobic SBA-PFDTS accelerated aggregation kinetics. Subsequently, we quantified the relative population of fibril structures formed in the presence of each material using electron microscopy. Fibrils formed from A{beta}1-40 exposed to SBA-PEG were structurally similar to control fibrils. In contrast, A{beta}1-40 incubated with SBA-15 or SBA-PFDTS formed fibrils with shorter cross-over distances that were more structurally representative of fibrils found in AD patient-derived samples. Overall, these results suggest that mesoporous silicas and other exogenous materials are promising scaffolds for the de novo production of specific fibril polymorphs of A{beta}1-40 and other amyloidogenic proteins. Significance StatementA major challenge in understanding the progression of Alzheimers Disease lies in the various fibril structures, or polymorphs, adopted by Amyloid-{beta} (A{beta}). Heterogenous fibril populations may be responsible for different disease phenotypes and growing evidence suggests that A{beta} fibrils formed in vitro are structurally distinct from patient-derived fibrils. To help bridge this gap, we used surface-functionalized mesoporous silicas to influence the formation of A{beta}1-40 fibrils and evaluated the distribution of resulting fibril polymorphs using electron microscopy (EM). We found that silicas modified with hydrophobic surfaces resulted in fibril populations with shorter cross-over distances that are more representative of A{beta} fibrils observed ex vivo. Overall, our results indicate that mesoporous silicas may be leveraged for the production of specific A{beta} polymorphs.

biochemistry↗