Biology subjects

Bhembre, N.

Publications and source records attributed to Bhembre, N..

4 recordsLinked to original sources

bioRxiv2025

Direct Evidence for Dendritic Spine Compensation and Regeneration in Alzheimer Disease Models

Dendritic spine loss in Alzheimers disease (AD) strongly correlates with cognitive decline, whereas spine preservation is associated to cognitive resilience. Yet, whether and how neurons compensate for spine loss in AD remains largely unknown. Using a chromophore-assisted light inactivation approach (CALI), we developed a tool to selectively eliminate dendritic spines to model this key feature of AD. Using in vivo and in vitro two-photon imaging, we discovered that the artificial elimination of spines triggers a two-stage compensatory response: rapid enlargement of remaining spines followed by delayed spine regeneration. Remarkably, similar structural plasticity was observed across multiple {beta}-amyloid-driven models of synapse loss, including the APP/PS1 mouse and following intracortical delivery of oligomeric {beta}-amyloid. Mechanistically, compensatory spine enlargement required NMDA receptor activation and de novo protein synthesis. These findings suggest that neurons retain an intrinsic capacity to reverse early synaptic loss in AD, potentially contributing to cognitive resilience.

neuroscience↗

bioRxiv2023

Copine-6 is a Ca2+ sensor for activity-induced AMPA receptor exocytosis

The recruitment of synaptic AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors underlies the strengthening of neuronal connectivity during learning and memory. This process is triggered by NMDA (N-methyl-D-aspartate) receptor-dependent postsynaptic Ca2+ influx. Synaptotagmin (Syt)-1 and -7 have been proposed as Ca2+-sensors for AMPA receptor exocytosis, but are functionally redundant. Here we identify a cytosolic C2 domain-containing Ca2+-binding protein Copine-6 that forms a complex with AMPA receptors. Loss of Copine-6 expression impairs activity-induced exocytosis of AMPA receptors in primary hippocampal neurons, which is rescued by wild-type Copine-6, but not Ca2+-binding mutants. In contrast, Copine-6 loss-of-function has no effects on steady-state expression or tetrodotoxin-induced synaptic upscaling of surface AMPA receptors. Loss of Syt-1/-7 significantly reduces Copine-6 protein expression. Interestingly, overexpression of wild-type Copine-6, but not the Ca2+-binding mutant, restores activity-dependent exocytosis of AMPA receptors in Syt-1/-7 double-knockdown neurons. We conclude that Copine-6 is a postsynaptic Ca2+-sensor that mediates AMPA receptor exocytosis during synaptic potentiation.

neuroscience↗

bioRxiv2022

Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates that reduce surface AMPA receptor expression in primary neurons

SFPQ is a nuclear RNA-binding protein that is involved in a wide range of physiological processes including neuronal development and homeostasis. However, the mislocalization and cytoplasmic aggregation of SFPQ are associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). We have previously reported that zinc mediates SFPQ polymerization and promotes the formation of cytoplasmic aggregates in neurons. Here we characterize two familial ALS (fALS)-associated SFPQ variants, which cause amino acid substitutions in the proximity of the SFPQ zinc-coordinating center (N533H and L534I). Both mutants display increased zinc-binding affinities, which can be explained by the presence of a secondary zinc-binding site revealed by the 1.83[A] crystal structure of the human SFPQ L534I mutant. Overexpression of these fALS-associated mutants significantly increases the number of SFPQ cytoplasmic aggregates in primary neurons. Although they do not affect the density of dendritic spines, the presence of SFPQ cytoplasmic aggregates causes a marked reduction in the levels of the GluA1, but not the GluA2 subunit of AMPA-type glutamate receptors on the neuronal surface. Taken together, our data demonstrate that fALS-associated mutations enhance the propensity of SFPQ to bind zinc and form aggregates, leading to the dysregulation of AMPA receptor subunit composition, which may contribute to neuronal dysfunction in ALS.

neuroscience↗

bioRxiv2019

The axonal actin-spectrin lattice acts as shock absorbers to protect neurons from stretch-induced damage

Axons are thin tubular extensions generated by neuronal cells to transmit signals across long distances. In the peripheral and the central nervous systems, axons experience large deformations during normal activity or as a result of injury. Yet, axon biomechanics, and its relation to the internal structure that allows axons to withstand such deformations, is poorly understood. Up to now, it has been generally assumed that microtubules and their associated proteins are the major load-bearing elements in axons. We revise this view point by combining mechanical measurements using a custom developed force apparatus with biochemical or genetic modifications to the axonal cytoskeleton, revealing an unexpected role played by the actin-spectrin skeleton. For this, we first demonstrate that axons exhibit a reversible strain-softening response, where its steady state elastic modulus decreases with increasing strain. We then explore the contributions from the various cytoskeletal components of the axon, and show that the recently discovered membrane-associated skeleton consisting of periodically spaced actin filaments interconnected by spectrin tetramers play a prominent mechanical role. Finally, using a theoretical model we argue that the actin-spectrin skeleton act as an axonal tension buffer by reversibly unfolding repeat domains of the spectrin tetramers to buffer excess mechanical stress.

biophysics↗