CDKL5's role in microtubule-based transport and cognitive function DOI Creative Commons
André T. Lopes,

Ondine Janiv,

Suzanne Claxton

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 29, 2024

Abstract Cyclin-dependent kinase like 5 (CDKL5) is a serine-threonine highly enriched in mammalian neurons. CDKL5 located on the X-chromosome and its loss-of-function leads to severe neurodevelopmental disorder called deficiency (CDD). phosphorylates microtubule-associated protein MAP1S regulates binding microtubules. How phosphorylation affects microtubule function not well understood. To address this question, we generated phosphomutant mice, which sites S786 S812 are mutated Alanine (MAP1S S786/812A or SA). Using co-sedimentation assay, showed that dynein microtubules severely reduced knockout (KO) SA brains. Time-lapse imaging primary neurons impaired motility both Cdkl5 KO SA. Dynein-driven cargo transport was affected mutant neuron dendrites, including delivery of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. We next studied tubulin tyrosination found mutants had when compared WT Since dynein-dynactin has higher affinity for tyrosinated microtubules, hypothesized mice could be mechanistic cause motility. In support this, show upon expression tyrosine TTL, rescued defects Hippocampal derived from revealed significant reduction spine density synapses, altered morphology. Finally, behavioral phenotyping increased anxiety, motor performance, social memory deficits, mirroring some extent clinical manifestations present CDD patients. Our results reveal an important contributor dynein-mediated synapse formation. Graphical abstract

Language: Английский

Announcing the JCS–David Stephens Prize and the 2024 winner Anja Konietzny DOI
Michael Way

Journal of Cell Science, Journal Year: 2025, Volume and Issue: 138(7)

Published: April 1, 2025

Language: Английский

Citations

0
A Methodology for Specific Disruption of Microtubule Polymerization into Dendritic Spines DOI
Elizabeth D. Holland, Hannah L. Miller,

Matthew M. Millette

et al.

Molecular Biology of the Cell, Journal Year: 2024, Volume and Issue: 35(6)

Published: April 17, 2024

Dendritic spines, the mushroom-shaped extensions along dendritic shafts of excitatory neurons, are critical for synaptic function and one first neuronal structures disrupted in neurodevelopmental neurodegenerative diseases. Microtubule (MT) polymerization into spines is an activity-dependent process capable affecting spine shape function. Studies have shown that MT occurs specifically undergoing plastic changes. However, discerning invasion requires specific inhibition while leaving dynamics shaft, synaptically connected axons associated glial cells intact. This not possible with unrestricted, bath application pharmacological compounds. To disrupt entry we coupled a elimination domain (MTED) from Efa6 protein to actin filament-binding peptide LifeAct. LifeAct was chosen because filaments highly concentrated necessary invasions. Temporally controlled expression this LifeAct-MTED construct inhibits preserving typical dendrite shaft. Expression will allow determination more broadly, discern how MT-actin interactions affect cellular processes.

Language: Английский

Citations

2
Unveiling the cell biology of hippocampal neurons with dendritic axon origin DOI
Yuhao Han, Daniela Hacker, Bronte Catharina Donders

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 224(1)

Published: Sept. 24, 2024

In mammalian axon-carrying–dendrite (AcD) neurons, the axon emanates from a basal dendrite, instead of soma, to create privileged route for action potential generation at initial segment (AIS). However, it is unclear how such unusual morphology established and whether structure function AIS in AcD neurons are preserved. By using dissociated hippocampal cultures as model, we show that development can occur prior synaptogenesis independently vivo environment. A single precursor neurite first gives rise then AcD. The possesses similar cytoskeletal architecture soma-derived similarly functions trafficking barrier retain axon-specific molecular composition. does not undergo homeostatic plasticity, contains lesser cisternal organelles, receives fewer inhibitory inputs. Our findings reveal insights into neuron biology underscore structural differences based on onset.

Language: Английский

Citations

2
CDKL5's role in microtubule-based transport and cognitive function DOI Creative Commons
André T. Lopes,

Ondine Janiv,

Suzanne Claxton

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 29, 2024

Abstract Cyclin-dependent kinase like 5 (CDKL5) is a serine-threonine highly enriched in mammalian neurons. CDKL5 located on the X-chromosome and its loss-of-function leads to severe neurodevelopmental disorder called deficiency (CDD). phosphorylates microtubule-associated protein MAP1S regulates binding microtubules. How phosphorylation affects microtubule function not well understood. To address this question, we generated phosphomutant mice, which sites S786 S812 are mutated Alanine (MAP1S S786/812A or SA). Using co-sedimentation assay, showed that dynein microtubules severely reduced knockout (KO) SA brains. Time-lapse imaging primary neurons impaired motility both Cdkl5 KO SA. Dynein-driven cargo transport was affected mutant neuron dendrites, including delivery of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. We next studied tubulin tyrosination found mutants had when compared WT Since dynein-dynactin has higher affinity for tyrosinated microtubules, hypothesized mice could be mechanistic cause motility. In support this, show upon expression tyrosine TTL, rescued defects Hippocampal derived from revealed significant reduction spine density synapses, altered morphology. Finally, behavioral phenotyping increased anxiety, motor performance, social memory deficits, mirroring some extent clinical manifestations present CDD patients. Our results reveal an important contributor dynein-mediated synapse formation. Graphical abstract

Language: Английский

Citations

0