Neuron with excessive branching, symbolizing hyperglutamylation.

Too Much of a Good Thing? How Overdoing a Key Brain Modification Leads to Neuron Problems

Avery Sinclair in Health & Wellness August 2025 • 4 min read.

"New research reveals how excessive glutamylation, a crucial modification in brain cells, can trigger neurodegeneration, offering potential targets for future therapies."

Microtubules, the structural filaments within our cells, are essential for maintaining cell architecture, including shape, polarity, and the transport of organelles. To support this wide array of functions, microtubules adapt their structure and dynamics based on cell type, developmental stage, and even the specific subset of microtubules within a single cell.

This specialization relies on the use of different tubulin isotypes, microtubule-associated proteins (MAPs), and post-translational modifications of tubulin. A key modification is polyglutamylation, where polyglutamate tails are added to the C-termini of α-tubulin or β-tubulin. This process involves adding a glutamic acid residue to a gene-encoded glutamate, and the resulting polypeptide chain can be elongated by further glutamate additions.

Two recent studies have shed light on the importance of this modification, demonstrating that excessive accumulation of polyglutamylation leads to neurodegeneration in both mice and humans. This groundbreaking research points to defects in axonal microtubule-based transport as a likely cause.

The Delicate Balance: Why Too Much Glutamylation is Harmful

Neuron with excessive branching, symbolizing hyperglutamylation.

Glutamylation is a reversible process, with glutamate residues being removed by members of the cytosolic carboxypeptidase (CCP) family. While tubulin is the primary target, other substrates are also known. Polyglutamylation affects the structure and increases the negative charge of tubulin tails, which are crucial for interactions with various MAPs. This modification is found on spindle and midbody microtubules during cell division and is enriched on centrioles, cilia, and neuronal microtubules.

The first clue that polyglutamylation levels are critical for neuronal function came from studies of the Purkinje cell degeneration (pcd) mouse model, which lacks functional CCP1. This deficiency leads to the degeneration of cerebellar Purkinje cells. Since CCP1 negatively regulates polyglutamylation, this research indicated that maintaining appropriate levels of this modification is essential for neuronal survival.

CCP1's Multifaceted Role: CCP1 removes polyglutamate chains and gene-encoded C-terminal acidic residues from proteins, including tubulin.
Unanswered Questions: Whether sensitivity to CCP1 levels is a general property of neurons, and the underlying mechanisms, remained unclear.

To address these questions, researchers combined conditional Purkinje cell-specific knockouts in genes encoding CCP1 and TTLL1, a major brain polyglutamylase. While the loss of CCP1 causes Purkinje cell death shortly after birth, deleting TTLL1 at the same time completely reversed this effect. Mice deficient in TTLL1 had significantly reduced levels of tubulin polyglutamylation.

From Mice to Humans: Implications for Neurodegenerative Disease

This research leads to several important conclusions. First, the toxicity of losing CCP1 activity is due to increased polyglutamylation, not the removal of gene-encoded glutamates. Second, increased, but not decreased, polyglutamylation compromises neuronal survival. Third, hyperglutamylation causes neuronal death in a cell-autonomous manner.

Intriguingly, studies have revealed that the loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration in humans, marked by abnormalities in the cerebellum, spinal motor neurons, and peripheral nerves – mirroring the pathology observed in the pcd mouse.

These findings strongly suggest that an impaired balance in microtubule polyglutamylation has a significant impact on neuronal survival in humans, opening avenues for therapies modulating the activity of enzymes controlling this modification to inhibit neurodegeneration.

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This article is based on research published under:

DOI-LINK: 10.15252/embj.2018101023, Alternate LINK

Title: More Is Not Always Better: Hyperglutamylation Leads To Neurodegeneration

Subject: General Immunology and Microbiology

Journal: The EMBO Journal

Publisher: EMBO

Authors: Anna Akhmanova, Casper C Hoogenraad

Published: 2018-11-23

Everything You Need To Know

What exactly is polyglutamylation and how does it relate to brain cells?

Polyglutamylation is a crucial modification process within brain cells, where glutamate molecules are added to tubulin proteins. These tubulin proteins are the building blocks of microtubules, which are essential for maintaining cell structure, shape, and transport within the cell. Excessive polyglutamylation can lead to neurodegeneration. This process involves the addition of polyglutamate tails to the C-termini of α-tubulin or β-tubulin.

Why is polyglutamylation considered so important, especially in the context of neuronal function?

The importance of polyglutamylation lies in its impact on microtubule function and neuronal health. The addition of polyglutamate tails alters the structure and increases the negative charge of tubulin, which influences its interactions with microtubule-associated proteins (MAPs). Proper regulation of polyglutamylation levels is vital because excessive accumulation of this modification has been shown to cause neurodegeneration in both mice and humans. The Purkinje cell degeneration (pcd) mouse model, which lacks functional CCP1, highlights the significance of maintaining proper levels of polyglutamylation. The loss of CCP1 activity leads to increased polyglutamylation and subsequent neuronal death.

What are the implications of having too much polyglutamylation, and what does this mean for health?

The implications of excessive polyglutamylation are significant, primarily because it has been linked to neurodegenerative diseases. Research shows that hyperglutamylation leads to neuronal death in a cell-autonomous manner, and defects in axonal microtubule-based transport is a likely cause. This process involves the addition of glutamate residues by enzymes, leading to the elongation of the polypeptide chain. Furthermore, studies on mice deficient in CCP1 and TTLL1 indicate that the toxicity associated with losing CCP1 activity is directly related to increased polyglutamylation, not the removal of gene-encoded glutamates. This finding opens the door to potential therapeutic strategies for neurodegenerative diseases.

What role does CCP1 play in the process of polyglutamylation?

CCP1, a member of the cytosolic carboxypeptidase family, plays a critical role in regulating polyglutamylation. It functions by removing polyglutamate chains from proteins, including tubulin. The absence of functional CCP1 leads to excessive polyglutamylation, which results in neuronal degeneration, as seen in the Purkinje cell degeneration (pcd) mouse model. The deletion of TTLL1, a major brain polyglutamylase, alongside the loss of CCP1, reversed the effect, indicating the role of CCP1 in maintaining appropriate levels of polyglutamylation is essential for neuronal survival. The balance of polyglutamylation is tightly controlled by the opposing actions of enzymes like CCP1 and the polyglutamylase TTLL1.

How do microtubules and their modification, polyglutamylation, relate to cell function and potential problems?

Microtubules, the structural filaments within cells, are essential for maintaining cell architecture and are involved in numerous cellular functions, including cell shape, polarity, and the transport of organelles. They adapt their structure and dynamics based on the cell type and developmental stage. Polyglutamylation directly influences these functions by altering the properties of tubulin, which is a primary component of microtubules. This modification affects the interaction of microtubules with MAPs, influencing their stability and function, thus contributing to their role in neuronal health and the processes related to neurodegeneration when dysregulated. The process takes place on the C-termini of α-tubulin or β-tubulin.