【Publications】ALS-associated protein TDP-43 disturbs axonal projections in the somatosensory cortex

July 16 2026

Published date
12 June 2026

Lab
Hidenobu Mizuno

Authors
Elvira Abzhanova, Yuzuki Kawae, Hiromi Mizuno, Terumasa Umemoto, Halilibrahim Ciftci, Masafumi Tsuboi, Yusuke Hirabayashi, Hidenobu Mizuno*

Title
ALS-associated protein TDP-43 disturbs axonal projections in the somatosensory cortex

Journal information
Neurosci. Res., 229, 105079. Advance online publication. https://doi.org/10.1016/j.neures.2026.105079
URL: https://www.sciencedirect.com/science/article/pii/S0168010226000660?via%3Dihub

Highlights
➢TDP-43 disrupts callosal axons of L2/3 neurons of somatosensory cortex in mice.
➢ALS-associated TDP-43 mutants show stronger axonal defects than WT TDP-43.
➢Fluorescently labeled TDP-43 is distributed as aggregates in the cytoplasm and neurites.
➢Postnatal tamoxifen-induced TDP-43 expression reduces axonal length and branching.

Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons that gradually causes muscle weakness and paralysis, eventually resulting in death. While ALS was once believed to specifically target motor neurons, recent clinical studies have revealed sensory involvement. The pathological hallmark of ALS is TAR DNA-binding protein 43 (TDP-43) aggregation in cytoplasm, with increasing evidence of its presence in both motor and sensory neurons. However, sensory abnormalities remain poorly characterized. To address this research gap, we analyzed the effects of TDP-43 expression on layer 2/3 (L2/3) pyramidal neurons of the primary somatosensory cortex in mice projecting through corpus callosum. In utero electroporation (IUE) was performed to express GFP alone (control) or in combination with TDP-43. Compared with the control, mice co-expressing GFP and TDP-43 showed disturbed callosal axonal projections of L2/3 neurons. Mutant TDP-43 variants displayed a more pronounced phenotype, indicating pathogenic role during fetal cortical development. To distinguish developmental from maintenance effects, tamoxifen-inducible TDP-43 expression was used to initiate postnatal TDP-43 expression. Postnatal induction resulted in shorter axonal length and reduced branching rather than gross projections disturbance. Taken together, these results demonstrate that TDP-43 expression can disturb the integrity of axonal projections, such as callosal projections of L2/3 neurons in the somatosensory cortex.

Graphical Abstract