α-tubulin tail modifications regulate microtubule stability through selective effector recruitment, not changes in intrinsic polymer dynamics

Chen, Jiayi; Kholina, Ekaterina G.; Szyk, Agnieszka; Fedorov, Vladimir A.; Kovalenko, I. B.; Gudimchuk, Nikita; Roll-Mecak, Antonina

doi:10.1016/j.devcel.2021.05.005

Cited by 68 publications

(81 citation statements)

References 142 publications

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“…STMN2 is a regulator of microtubule and axonal stability that was recently found to be a rare genetic cause of ALS 42 and may be a major downstream mediator of TDP-43 function in axon degeneration 43, 69, 70 . TUBA4A is an unusual tubulin isoform that lacks a critical tyrosine site for regulating microtubule dynamics and is thus a constituitively stable α - tubulin variant 71 and TUBA4A variants are associated with ALS genetically 15 . A robust cytoskeleton may be important in human motoneurons to facilitate axonal transport of mitochondria, protein, and RNA in the long motoneuron axon 61 or may provide structural support to protect motoneuron axons against microtears and stretching during body movement.…”

Section: Discussionmentioning

confidence: 99%

A Cellular Taxonomy of the Adult Human Spinal Cord

Yadav

Matson

et al. 2022

Preprint

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In neurodegenerative diseases of the human spinal cord, such as amyotrophic lateral sclerosis (ALS), motoneurons are particularly vulnerable to degeneration. It is hypothesized that their large size contributes to disease susceptibility, but the link between genetic variants associated with disease and cell-type specific degeneration is not clear. We characterized human spinal cord cells using single-nucleus RNA-sequencing and protein profiling. We found that human motoneurons displayed a unique expression profile characterized by factors involved in cytoskeletal structure, cell size, and degenerative disease (including ALS-associated genes SOD1, NEFH, OPTN, TUBA4A, PRPH, and STMN2) and that protein expression of these genes correlated with larger cell size in tissue. This work suggests a motoneuron-specific signature underlies their selective vulnerability to neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

A Cellular Taxonomy of the Adult Human Spinal Cord

Yadav

Matson

et al. 2022

Preprint

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“…To drive the proteins off the microtubule shaft and enrich them at the growing tip we increased the salt concentrations (for details see methods) (Telley et al, 2011;Bieling et al, 2014;Chen et al, 2021). As a first step, we reconstituted microtubule growth in presence of a +TIP-network, with either reduced (50 nM H2 + 1.8 µM EB3) or minimal (50 nM H1 + 1.8 µM EB3) LLPS activity (Figure 3D), implying reduced or no co-condensation of tubulin at the growing tip (Figure 4C).…”

Section: The Transition From +Tip-network To +Tip-droplets Accelerates Microtubule Growthmentioning

confidence: 99%

“…After GTP-tubulin addition, GTP is gradually hydrolyzed, resulting in a GDP-tubulin shaft behind the tip. Once the stabilizing GTP-tubulin “cap” disappears from the plus-end, the microtubule switches from growing to shrinking, an event termed catastrophe (Howard and Hyman, 2009; Brouhard et al, 2015; Gudimchuk and McIntosh, 2021). Conversely, microtubules can stop shrinking and switch to regrowth, an event termed rescue.…”

Section: Introductionmentioning

confidence: 99%

Phase separation of +TIP-networks regulates microtubule dynamics

Miesch

Wimbish

Velluz

et al. 2021

Preprint

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Tubulin dimers assemble into a dynamic microtubule network throughout the cell. Microtubule dynamics and network organization must be precisely tuned for the microtubule cytoskeleton to regulate a dazzling array of dynamic cell behaviors. Since tubulin concentration determines microtubule growth, we studied here a novel regulatory mechanism of microtubule dynamics: local tubulin condensation. We discovered that two microtubule tip-binding proteins, CLIP-170 and EB3, undergo phase separation and form an EB3/CLIP-170 droplet at the growing microtubule tip. We prove that this +TIP-droplet has the capacity to locally condense tubulin. This process of tubulin co-condensation is spatially initiated at the microtubule tip and temporally regulated to occur only when there is tip growth. Tubulin condensation at the growing microtubule tip increases growth speeds three-fold and strongly reduces depolymerization events. With this work we establish a new mechanism to regulate microtubule dynamics by enrichment of tubulin at strategically important locations: the growing microtubule tips.

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“…To drive the proteins off the microtubule shaft and enrich them at the growing tip we increased the salt concentrations (for details see methods) (Telley et al, 2011;Bieling et al, 2014;Chen et al, 2021). As a first step, we reconstituted microtubule growth in presence of a +TIP-network, with either reduced (50 nM H2 + 300 nM EB3) or minimal (50 nM H1 + 300 nM EB3) LLPS activity (Figure 3D), implying reduced or no co-condensation of tubulin at the growing tip (Figure 4C).…”

Section: The Transition From +Tip-network To +Tip-droplets Accelerate...mentioning

confidence: 99%

A liquid +TIP-network drives microtubule dynamics through tubulin condensation

Aumeier

2022

Biophysical Journal

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α-tubulin tail modifications regulate microtubule stability through selective effector recruitment, not changes in intrinsic polymer dynamics

Cited by 68 publications

References 142 publications

A Cellular Taxonomy of the Adult Human Spinal Cord

A Cellular Taxonomy of the Adult Human Spinal Cord

Phase separation of +TIP-networks regulates microtubule dynamics

A liquid +TIP-network drives microtubule dynamics through tubulin condensation

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