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Hypermethylation of FGF13 Reduces Microtubule Stability via Interaction With TUBB2A to Promote Mitochondrial

Dan Ren¹, Hong Zhu¹, Ting Zhang¹

¹Department of Traditional Chinese Medicine, The Third Xiangya Hospital of Central South University, Changsha City, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology

|March 11, 2026

Abstract:

Alzheimer's disease (AD) represents a primary contributor to cognitive deterioration in the elderly population. Mitochondrial dysfunction, which is closely associated with microtubule instability, contributes to AD progression. TUBB2A, a key microtubule protein, is essential for mitochondrial transport and neuronal function. This study investigates how DNA methylation of FGF13 affects mitochondrial function and its role in AD via the FGF13/TUBB2A axis. AD mouse models were established by injecting Aβ_25-35 into the hippocampus, and dual-fluorescence staining was employed to quantify the expression levels of FGF13 and TUBB2A in different neural cell types in brain tissue. Western blotting assessed microtubule stability and mitochondrial function in the hippocampus. Nissl and TUNEL staining were used to detect neuronal survival and apoptosis, and transmission electron microscopy was used to observe the ultrastructure of mitochondria. Flow cytometry was employed to determine mitochondrial membrane potential in hippocampal tissue, and Methylation-Specific PCR was used to detect the methylation levels of FGF13. Co-immunoprecipitation experiments verified the interaction between FGF13 and TUBB2A. Mitochondrial dysfunction exists in the hippocampal tissue of AD mice. Overexpression of FGF13 alleviated mitochondrial ROS, enhanced microtubule stability, increased mitochondrial membrane potential, and reduced neuronal apoptosis, thereby improving symptoms. FGF13 was found to be methylated, and its methylation affected its direct binding with TUBB2A. Overexpression of FGF13's protective effects on neurons could be reversed by knocking down TUBB2A. The expression of FGF13 is reduced in AD mouse neurons, which is associated with its high methylation state. Overexpression of FGF13 improves microtubule stability and mitochondrial function in hippocampal neurons through interaction with TUBB2A, suggesting a potential therapeutic relevance in AD.

Insights

This study reveals that reduced FGF13, due to DNA methylation, impairs microtubule stability and mitochondrial function in Alzheimer's disease (AD). Restoring FGF13 improves neuronal health and cognitive function in AD mouse models.

Area of Science:

Neuroscience
Molecular Biology
Genetics

Background:

Alzheimer's disease (AD) is a leading cause of age-related cognitive decline.
Mitochondrial dysfunction and microtubule instability are key contributors to AD pathogenesis.
The microtubule protein TUBB2A plays a critical role in mitochondrial transport and neuronal function.

Purpose of the Study:

To investigate the role of FGF13 DNA methylation in Alzheimer's disease.
To elucidate the FGF13/TUBB2A axis in regulating mitochondrial function and neuronal survival in AD.
To explore FGF13 as a potential therapeutic target for AD.

Main Methods:

Establishment of AD mouse models using Aβ25-35 hippocampal injection.
Dual-fluorescence staining, Western blotting, Nissl, TUNEL, and transmission electron microscopy for cellular and mitochondrial analysis.
Methylation-Specific PCR and co-immunoprecipitation to assess FGF13 methylation and FGF13/TUBB2A interaction.

Main Results:

Mitochondrial dysfunction and neuronal apoptosis were observed in AD mouse hippocampi.
FGF13 overexpression ameliorated mitochondrial dysfunction, enhanced microtubule stability, and reduced neuronal apoptosis.
FGF13 methylation was increased in AD neurons, inversely correlating with FGF13 expression and affecting its binding to TUBB2A.

Conclusions:

Reduced FGF13 expression, linked to increased DNA methylation, contributes to AD pathology by disrupting microtubule stability and mitochondrial function.
FGF13 exerts neuroprotective effects via interaction with TUBB2A, suggesting therapeutic potential for AD.

Read full analysis

Keywords:

Alzheimer's disease FGF13 TUBB2A methylation mitochondria

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