Biology subjects

Paras, N. A.

Publications and source records attributed to Paras, N. A..

3 recordsLinked to original sources

bioRxiv2024

Structure of a novel α-synuclein filament fold from multiple system atrophy

Multiple system atrophy (MSA) is a synucleinopathy, a group of related diseases characterized by the accumulation of -synuclein aggregates in the brain. In MSA, these aggregates form glial cytoplasmic inclusions, which contain abundant cross-{beta} amyloid filaments. Structures of -synuclein filaments isolated from MSA patient tissue were determined by cryo-electron microscopy (cryo-EM), revealing three discrete folds that are distinct from -synuclein filaments associated with other synucleinopathies. Here, we use cryo-EM classification methods to characterize filaments from one individual with MSA and identify a novel, low-populated MSA filament fold (designated Type I2) in addition to a predominant class comprising MSA Type II2. The 3.3-[A] resolution structure of the Type I2 filament reveals a fold consisting of two asymmetric protofilaments. One is identical to a previously solved Type I protofilament, while the second adopts a novel fold that is chimeric between two previously reported Type I and II protofilaments. These results further define disease-specific folds of -synuclein filaments that develop in MSA and have implications for the design of therapeutic and diagnostic molecules that target disease.

biophysics↗

bioRxiv2022

Stacked binding of a small molecule PET tracer to Alzheimer's tau paired helical filaments

Neurodegenerative diseases (NDs) are characterized by the formation of amyloid filaments that adopt disease-specific conformations in the brain. Recently developed small molecules hold promise as diagnostics and possible therapeutics for NDs, but their binding mechanisms to amyloid filaments remain unknown. Here, we used cryo-electron microscopy (cryo-EM) to determine a 2.7 [A] structure of Alzheimers disease patient-derived tau paired-helical filaments incubated with the GTP-1 PET probe. GTP-1 is bound stoichiometrically along an exposed cleft of each protofilament in a stacked arrangement that matches the fibrils symmetry. Multiscale modeling revealed favorable pi-pi aromatic stacking interactions between GTP-1 molecules that, together with small molecule-protein contacts, result in high affinity binding. This binding mode offers new insight into designing compounds for diagnosis and treatment of specific NDs. One Sentence SummaryCryo-EM structure reveals a novel stacked arrangement of the GTP-1 PET ligand bound to Alzheimers disease tau filaments.

biophysics↗

bioRxiv2021

Trans-channel fluorescence learning improves high-content screening for Alzheimer's disease therapeutics

In microscopy-based drug screens, fluorescent markers carry critical information on how compounds affect different biological processes. However, practical considerations may hinder the use of certain fluorescent markers. Here, we present a deep learning method for overcoming this limitation. We accurately generated predicted fluorescent signals from other related markers and validated this new machine learning (ML) method on two biologically distinct datasets. We used the ML method to improve the selection of biologically active compounds for Alzheimers disease (AD) from high-content high-throughput screening (HCS). The ML method identified novel compounds that effectively blocked tau aggregation, which would have been missed by traditional screening approaches unguided by ML. The method improved triaging efficiency of compound rankings over conventional rankings by raw image channels. We reproduced this ML pipeline on a biologically independent cancer-based dataset, demonstrating its generalizability. The approach is disease-agnostic and applicable across diverse fluorescence microscopy datasets.

pharmacology and toxicology↗