Inflammation Induces TDP-43 Mislocalization and Aggregation.

Ana Sofia Correia,Jean-Pierre Julien,Kallol Dutta,Priyanka Patel

doi:10.1371/journal.pone.0140248

Abstract

TAR DNA-binding protein 43 (TDP-43) is a major component in aggregates of ubiquitinated proteins in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we report that lipopolysaccharide (LPS)-induced inflammation can promote TDP-43 mislocalization and aggregation. In culture, microglia and astrocytes exhibited TDP-43 mislocalization after exposure to LPS. Likewise, treatment of the motoneuron-like NSC-34 cells with TNF-alpha (TNF-α) increased the cytoplasmic levels of TDP-43. In addition, the chronic intraperitoneal injection of LPS at a dose of 1mg/kg in TDP-43A315T transgenic mice exacerbated the pathological TDP-43 accumulation in the cytoplasm of spinal motor neurons and it enhanced the levels of TDP-43 aggregation. These results suggest that inflammation may contribute to development or exacerbation of TDP-43 proteinopathies in neurodegenerative disorders.

Highlights

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of motor neurons in the brain and spinal cord, causing progressive muscle weakness and typically leading to death by paralysis within a few years
As schematic representation of the approaches is shown in S1 Fig. Morphological changes of astrocytes and microglia to LPS treatment confirmed the activation of those cells
Microglia from C57Bl6 mice and from hTDP-43A315T transgenic mice went from a ‘resting’ form with long branching processes and small cellular body, in the absence of LPS, to a large ameboid form when treated with LPS (Fig 1A)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of motor neurons in the brain and spinal cord, causing progressive muscle weakness and typically leading to death by paralysis within a few years. Mutations in over twenty genes are known to be associated with familial forms of ALS [1,2] which account for 10% of all ALS cases. In both familial and sporadic ALS, degenerating neurons are known to present an abnormal accumulation of cytoplasmic inclusions containing ubiquitinated proteins [3]. In degenerating neurons of patients with ALS and FTLD, TDP-43 accumulates in the cytoplasm and forms insoluble aggregates in the nucleus, cytoplasm or processes [4, 7].

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Results

Conclusion