TDP-43 dysfunction destabilizes glial homeostatic identity in ALS/FTD

28/10/2026

AI Summary

Glial TDP-43 dysfunction destabilises lineage-specific homeostatic programmes in astrocytes, microglia, and oligodendrocytes, driving distinct pathological state transitions.
Astrocytes lose neurotransmitter handling, metabolic and RNA support; microglia show phagocytosis, lysosomal and lipid defects; oligodendrocytes lose RNA processing, myelin and axonal support.
A cross-glial framework integrating cell-autonomous dysfunction, non-cell-autonomous signalling, disease stage and genetic context is essential to understand TDP-43 proteinopathy.

TL;DR (AI Generated)

In this review, we examine how TDP-43 dysfunction disrupts lineage-specific glial homeostatic programs and promotes distinct pathological state transitions across major glial populations.

Together, these findings suggest that glial TDP-43 dysfunction cannot be reduced to a single generalized form of reactivity but instead reflects the breakdown of distinct cell type-specific identities required to maintain central nervous system homeostasis.

A cross-glial framework integrating cell-autonomous dysfunction, non-cell-autonomous signaling, disease stage, and genetic context may therefore provide a more complete understanding of TDP-43 proteinopathy and its contribution to neurodegeneration across the ALS-FTD spectrum.

Basic summary

Brain Res. 2026 Oct 27:150618. doi: 10.1016/j.brainres.2026.150618. Online ahead of print.

ABSTRACT

TAR DNA-binding protein 43 (TDP-43) pathology is a defining feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysfunction has traditionally been studied through a neuron-centric framework, increasing evidence demonstrates that astrocytes, microglia, and oligodendrocytes are also directly affected and actively contribute to disease progression. In this review, we examine how TDP-43 dysfunction disrupts lineage-specific glial homeostatic programs and promotes distinct pathological state transitions across major glial populations. In astrocytes, TDP-43 dysfunction impairs neurotransmitter regulation, metabolic and neuronal support, RNA homeostasis, and secretory signaling while promoting inflammatory and antiviral-like states. In microglia, altered TDP-43 disrupts inflammatory regulation, phagocytosis, lysosomal function, lipid metabolism, and stage-dependent protective responses. In oligodendrocytes, TDP-43 dysfunction compromises RNA processing, lineage maintenance, lipid metabolism, myelin integrity, and long-term axonal support. Together, these findings suggest that glial TDP-43 dysfunction cannot be reduced to a single generalized form of reactivity but instead reflects the breakdown of distinct cell type-specific identities required to maintain central nervous system homeostasis. A cross-glial framework integrating cell-autonomous dysfunction, non-cell-autonomous signaling, disease stage, and genetic context may therefore provide a more complete understanding of TDP-43 proteinopathy and its contribution to neurodegeneration across the ALS-FTD spectrum.

PMID:42946239 | DOI:10.1016/j.brainres.2026.150618

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