Biology subjects

De Silva, N.

Publications and source records attributed to De Silva, N..

3 recordsLinked to original sources

bioRxiv2026

A Versatile AAV-TH-SNCA Model to Study Early α-Synuclein Pathology and Intervention

Adeno-associated viral (AAV)-mediated overexpression of human wildtype -synuclein (-syn) in the substantia nigra (SN) is a widely used approach to model Parkinsons disease (PD) in rodents. However, variability in the ability of AAV-based systems to induce nigrostriatal pathology and motor deficits has limited reproducibility across studies, especially in mice. Here, we systematically optimized key vector features - AAV serotype, promoter, viral titer - to establish a highly efficient and reliable mouse model of PD. We compared the tropism and expression efficiency of mixed AAV2/1 and AAV2/rh10 serotypes combined with three promoters - CMV enhancer/chicken {beta}-actin (CBA), human Synapsin (hSYN), and rat Tyrosine Hydroxylase (TH) - to drive human -syn gene (SNCA) expression in nigral dopaminergic neurons. The AAV.TH.SNCA vector, delivered at an optimized titer, achieved selective and sustained -syn overexpression in nigral neurons, resulting in nigro-striatal neurochemical changes and progressive motor deficits preceding overt neuronal loss. Fine tuning -syn expression proved critical for detecting early disease processes: lower AAV.TH.SNCA titer induced early pathological signatures, including -syn hyperphosphorylation and neuroinflammation, whereas higher titers produced robust nigrostriatal degeneration not achieved with other promoter constructs. Notably, we demonstrate that motor and neurochemical impairments can occur prior to dopaminergic cell death, implicating microglial activation and -syn pathology as primary drivers of dysfunction. This observation is consistent with human genetic evidence showing that triplication of the wild-type SNCA gene alone can cause Parkinsonian pathology, highlighting that our model enables the use of a single experimental reagent to investigate the molecular, cellular, and behavioral consequences of controlled increases in -syn expression. This novel AAV.TH.SNCA model provides a powerful and versatile platform for investigating mechanisms of a -syn-mediated neurotoxicity and for evaluating disease modifying interventions targeting early, pre-degenerative stages of PD. HighlightsO_LITitrated -syn expression uncouples early dysfunction from dopaminergic neuron loss C_LIO_LIAAV2/rh10-TH-SNCA model captures prodromal and degenerative PD stages C_LIO_LIMotor deficits arise from -syn pathology and nigral molecular changes before neurodegeneration C_LI

neuroscience↗

bioRxiv2025

MDZip: Neural Compression of Molecular Dynamics Trajectories for Scalable Storage and Ensemble Reconstruction

The size of molecular dynamics (MD) trajectories remains a major obstacle for data sharing, long-term storage, and ensemble analysis at scale. Existing solutions often rely on frame subsampling or reduced atom representations, which limit the utility of shared datasets. Here, we present MDZip, a neural compression framework based on convolutional autoencoders trained per system to reconstruct atomic trajectories with high geometric fidelity from compact latent representations. MDZip achieves over 95% reduction in storage size across a diverse benchmark of proteins, protein-peptide complexes, and nucleic acids. Despite operating in a physics-agnostic manner, the reconstructed trajectories accurately preserve ensemble-level features, including RMSD fluctuations, pairwise distance distributions, radius of gyration, and projections onto principal and time-lagged independent components. A residual (skip-connected) autoencoder variant consistently improves reconstruction accuracy and reduces outliers. While local structural deviations can impair energetic fidelity, short energy minimization partially recovers physically reasonable conformations. This framework enables customizable compression-accuracy trade-offs and supports a modular workflow for sharing latent representations, decoder models, and reconstruction protocols. MDZip offers a scalable solution to current storage limitations, facilitating broader dissemination of MD data without sacrificing essential dynamical information.

biophysics↗

bioRxiv2024

The Arp2/3 complex maintains genome integrity and survival of epidermal Langerhans cells

Myeloid cells use intracellular actin networks for key cellular processes, including cell migration and chemotaxis, phagocytosis or macropinocytosis, as well as immune synapse formation. However, whether actin networks play any role in the development and/or survival of myeloid cells in tissues remains open. Here, we found that the Arp2/3 complex, which is responsible for the nucleation of branched actin networks, is needed for in vivo maintenance of epidermal Langerhans cells (LCs) throughout life. Mice harboring a genetic deletion of the Arpc4 subunit of the complex in myeloid cells form LC networks at birth, but these cells decline in numbers following a process reminiscent of premature cellular aging. By combining in vivo analyses of LCs with in vitro experiments on bone-marrow-derived dendritic cells, we found that Arpc4-deficient cells manage to progress through the cell cycle but accumulate DNA damage associated with aberrant nuclear shapes, lamina reduction and events of nuclear envelope rupture. These results provide the first evidence for a physiological role of Arp2/3 in maintenance of genome integrity and survival of immune cells in tissues.

cell biology↗