Neuronal remodeling is driven by polyglutamylation

This is a summary of Gavoci, A., Zhiti, A., Rusková, M. et al. Polyglutamylation of microtubules drives neuronal remodeling. Nat Commun 16, 5384 (2025). https://doi.org/10.1038/s41467-025-60855-6

The challenge

The brain, particularly during postnatal development and adolescence, undergoes a process called synaptic pruning, where it eliminates unnecessary or weak synaptic connections and the neurites that form them to establish a precisely wired neural circuit. During this process, the fate of otherwise indistinguishable neurites and synapses that are in the immediate vicinity of each other can vary significantly: while some are quickly removed, others can last for a lifetime. The microtubule cytoskeleton, which provides shape and support to cells—acting like a skeleton inside the cell—and facilitates organelle transport, plays a crucial role in these remodeling processes. As axon branches are pruned, microtubules are also removed, and post-translational modifications (PTMs) are modified. However, it remains unclear whether these changes in the cytoskeleton are instructive or merely a result of the breakdown process. This is why we investigated the role of a specific type of PTM during pruning: microtubule polyglutamylation.

Our approach

We used mouse models to systematically investigate the role of microtubule polyglutamylation during the process of synaptic pruning, specifically at the neuromuscular junction. In mice, this synapse transitions from being innervated by multiple axon branches to being innervated by a single axon branch within a few days.

Our findings

We discovered that tubulin polyglutamylation plays an important role in synaptic remodeling. Specifically, our findings indicate that during the pruning of motor axon branches, the polyglutamylation of tubulin alpha-4A (Tuba4a) occurs due to a balanced action between the "writer" enzyme, tubulin tyrosine ligase-like glutamylase 1 (TTLL1), and the "eraser" enzymes, cytosolic carboxypeptidases (CCP) 1 and 6. The local density of polyglutamyl side chains on microtubules determines the efficiency of spastin-mediated severing. We discovered that this interplay between PTMs and microtubule severing regulates the speed at which peripheral synapses remodel, and we confirmed a similar mechanism for the timing of axon and spine pruning in the developing hippocampus. In more technical terms, tubulin polyglutamylation serves as a cytoskeletal rheostat of remodeling that shapes neuronal morphology and connectivity.

The implications

Many of the enzymes involved in the remodeling mechanism described here are associated with neurodegenerative diseases. For example, Spastin is linked to hereditary spastic paraplegia, CCP1 to infantile-onset neurodegeneration, and Tuba4a to motor neuron disease. A common mechanism may involve changes in microtubule dynamics, which can lead to disrupted transport of organelles and enzymes, further affecting cytoskeletal stability. Therefore, understanding developmental neurite remodeling could help us develop strategies for targeting microtubules in cases of axon degeneration, particularly by focusing drug development on polyglutamylation.

Creating SyNergies

The study was led by our members Monika Leischner-Brill and Thomas Misgeld. A follow-up project is planned, in which they want to find the link between microtubule and PTM changes and neurotransmission, the main driver of synapse elimination — for this, they will collaborate with our Technology Hubs for RNA sequencing.