Biology subjects

Weissova, R.

Publications and source records attributed to Weissova, R..

4 recordsLinked to original sources

bioRxiv2025

Prolyl isomerase FKBP12 reduces axon growth and negatively regulates microtubule polymerization by inhibiting CRMP2A

Prolyl isomerases are enzymes catalyzing conformational change of the peptide bond between proline and the preceding amino acid, regulating the function and stability of their substrates. We have previously identified CRMP2A - the longer isoform of a microtubule-associated protein Collapsin response mediator protein 2 - as a substrate of the phospho-specific prolyl isomerase Pin1. CRMP2A is negatively regulated and destabilized by CDK5 phosphorylation in the distal axons and growth cones. Pin1 specifically binds to phosphorylated CRMP2A and stabilizes it by inducing conformational changes. However, the conformational regulation of unphosphorylated CRMP2 remains unknown. Here, we show that the prolyl isomerase FKBP12 specifically binds to unphosphorylated CRMP2A and regulates its activity. Using in vitro microtubule polymerization assays we demonstrate that CRMP2A promotes microtubule growth and that this function is inhibited by FKBP12. Next, using GFP-EB3 microtubule plus-end tracking assay, we demonstrate that FKBP12 inhibits CRMP2A-mediated microtubule polymerization also in cells. Furthermore, we show that FKBP12 co-localizes with unphosphorylated CRMP2A in growth cones and that expression of FKBP12 reduces axon growth in microfluidic chambers, while FKBP12 knockdown enhances it. Together, we demonstrate that FKBP12 is a negative regulator of microtubule dynamics and axon growth. Moreover, we show that two prolyl isomerases can differentially (positively or negatively) regulate activity of a common substrate depending on its phosphorylation. This provides an additional layer of phosphorylation-dependent or -independent control of protein activity, microtubule dynamics, and neuronal growth. Given the broad substrate specificity of FKBP12 and Pin1, this regulatory mechanism likely contributes to the modulation of diverse proteins and cellular processes in the nervous system and beyond.

neuroscience↗

bioRxiv2024

Tau phosphorylation impedes functionality of protective tau envelopes

Tau, an axonal microtubule-associated protein, is a critical regulator of microtubule function and stability. Tau interaction with microtubules is regulated by tau phosphorylation. Tau hyperphosphorylation is implicated in microtubule destabilization related to neurodegenerative disorders. How tau phosphorylation leads to microtubule destabilization is however unknown. Recently, it was shown that tau molecules on microtubules cooperatively assemble into cohesive layers termed envelopes. Tau envelopes protect microtubules against degradation by microtubule-severing enzymes, suggesting a functional link between envelopes and microtubule stability. Here we show that tau phosphorylation has deleterious effects on the microtubule-protective function of tau envelopes. Using reconstitution and live-cell experiments, we found that tau phosphorylation destabilizes tau envelopes and decreases their integrity, leading to reduced microtubule protection against microtubule-severing enzymes. Our data suggest that a perturbation of microtubule homeostasis linked to tau hyperphosphorylation in neurodegeneration, could be explained by the disassembly and impaired functionality of the tau envelopes.

cell biology↗

bioRxiv2019

Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with selective dysfunction; it causes the death of motor neurons (MNs). In spite of some progress, currently no effective treatment is available for ALS. Before such treatment can be developed, a more thorough understanding of ALS pathogenesis is required. Recently, we demonstrated that ALS-mutated muscles contribute to ALS pathology via secretion of destabilizing factors such as Sema3A; these factors trigger axon degeneration and Neuromuscular Junction (NMJ) disruption. Here, we focus on the molecular mechanism by which muscle contribute to MNs loss in ALS. We identified CRMP4 as part of a retrograde death signal generated in response to muscle-secreted Sema3A, in ALS-diseased MNs. Exposing distal axons to Sema3A induces CRMP4-dynein complex formation and MN loss in both mouse (SOD1G93A) and human-derived (C9orf72) ALS models. Introducing peptides that interfere with CRMP4-dynein interaction in MN axons profoundly reduces Sema3A-dependent MN loss. Thus, we discovered a novel retrograde death signal mechanism underlying MN loss in ALS.\n\nSummaryMaimon et al. identify a novel retrograde death mechanism that contribute to MN loss in ALS, in which CRMP4-Dynein complex is form and retrogradely move along the axon.

neuroscience↗

bioRxiv2019

CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling

Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins is key to development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating Semaphorin 3A (Sema3A) signaling and its dysfunction has been linked to schizophrenia, however, nothing is known about its role in the synapse pruning. Here, using newly generated crmp2-/- mice we demonstrate that while CRMP2 has only a moderate effect on Sema3A-dependent axon guidance in vivo, it is essential for Sema3F-dependent axon pruning and dendritic spine remodeling. We first demonstrate that CRMP2 deficiency interferes with Sema3A signaling in compartmentalized neuron cultures and leads to a mild defect in axon guidance in peripheral nerves and corpus callosum. Strikingly, we show that crmp2-/- mice display more prominent defects in dendritic spine pruning and stereotyped axon pruning in hippocampus and visual cortex consistent with impaired Sema3F signaling and with autism spectrum disorder (ASD)-rather than schizophrenia-like phenotype. Indeed, we demonstrate that CRMP2 mediates Sema3F-induced axon retraction in primary neurons and that crmp2-/- mice display early postnatal behavioral changes linked to ASD. In conclusion, we demonstrate that CRMP2 is an essential mediator of Sema3F-dependent synapse pruning and its dysfunction in early postnatal stages shares histological and behavioral features of ASD.

neuroscience↗