Biology subjects

French, R. L.

Publications and source records attributed to French, R. L..

3 recordsLinked to original sources

bioRxiv2025

TDP-43 Aggregate Seeding Impairs Autoregulation and Causes TDP-43 Dysfunction

The aggregation, cellular mislocalization and dysfunction of TDP-43 are hallmarks of multiple neurodegenerative disorders. We find that inducing TDP-43 aggregation through prion-like seeding gradually diminishes normal TDP-43 nuclear localization and function. Aggregate-affected cells show signature features of TDP-43 loss of function, such as DNA damage and dysregulated TDP-43-target expression. We also observe strong activation of TDP-43-controlled cryptic exons in cells, including human neurons treated with proteopathic seeds. Furthermore, aggregate seeding impairs TDP-43 autoregulation, an essential mechanism controlling TDP-43 homeostasis. Interestingly, proteins that normally interact with TDP-43 are not recruited to aggregates, while other factors linked to TDP-43 pathology, including Ataxin 2, specifically colocalize to inclusions and modify seeding-induced aggregation. Our findings indicate that TDP-43 aggregation, mislocalization and loss of function are strongly linked and suggest that disruption of TDP-43 autoregulation establishes a toxic feed-forward mechanism that amplifies aggregation and may be central in mediating this pathological connection.

cell biology↗

bioRxiv2022

Scene-relative object motion biases depth percepts

An important function of the visual system is to represent 3D scene structure from a sequence of 2D images projected onto the retinae. During observer translation, the relative image motion of stationary objects at different distances (motion parallax) provides potent depth information. However, if an object moves relative to the scene, this complicates the computation of depth from motion parallax since there will be an additional component of image motion related to scene-relative object motion. To correctly compute depth from motion parallax, only the component of image motion caused by self-motion should be used by the brain. Previous experimental and theoretical work on perception of depth from motion parallax has assumed that objects are stationary in the world. Thus, it is unknown whether perceived depth based on motion parallax is biased by object motion relative to the scene. Naive human subjects viewed a virtual 3D scene consisting of a ground plane and stationary background objects, while lateral self-motion was simulated by optic flow. A target object could be either stationary or moving laterally at different velocities, and subjects were asked to judge the depth of the object relative to the plane of fixation. Subjects showed a far bias when object and observer moved in the same direction, and a near bias when object and observer moved in opposite directions. This pattern of biases is expected if subjects confound image motion due to self-motion with that due to scene-relative object motion. These biases were large when the object was viewed monocularly, and were greatly reduced, but not eliminated, when binocular disparity cues were provided. Our findings establish that scene-relative object motion can confound perceptual judgements of depth during self-motion.

neuroscience↗

bioRxiv2018

TDP-43 oligomers detected as initial intermediate species during aggregate formation

Aggregates of the RNA binding protein TDP-43 are a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which are neurodegenerative disorders with overlapping clinical, genetic and pathological features. Mutations in the TDP-43 gene are causative of ALS, supporting its central role in pathogenesis. The process of TDP-43 aggregation remains poorly understood and whether this includes formation of intermediate complexes is unknown. We characterized aggregates derived from purified TDP-43 as a function of time and analyzed them under semi-denaturing conditions. Our assays identified oligomeric complexes at the initial time points prior to the formation of large aggregates, suggesting that ordered oligomerization is an intermediate step of TDP-43 aggregation. In addition, we analyzed liquid-liquid phase separation of TDP-43 and detected similar oligomeric assembly upon the maturation of liquid droplets into solid-like fibrils. These results strongly suggest that the oligomers form during the early steps of TDP-43 misfolding. Importantly, ALS-linked mutations A315T and M337V significantly accelerate aggregation, rapidly decreasing the monomeric population and shortening the oligomeric phase. We also show that the aggregates generated from purified protein seed intracellular aggregation, which is detected by established markers of TDP-43 pathology. Remarkably, cytoplasmic aggregate propagation is detected earlier with A315T and M337V and is 50% more widespread than with wild-type aggregates. Our findings provide evidence for a controlled process of TDP-43 self-assembly into intermediate structures that provide a scaffold for aggregation. This process is altered by ALS-linked mutations, underscoring the role of perturbations in TDP-43 homeostasis in protein aggregation and ALS-FTD pathogenesis.

biochemistry↗