Abstract

TAR DNA-binding protein of 43 kDa (TDP-43) is a major component of intracellular aggregates formed in brains of the patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), which are correctively referred to as TDP-43 proteinopathies. A link between Ataxin-2 (ATXN2) and TDP-43 proteinopathies was established when intermediate CAG repeat expansions of ATXN2 gene were found to be associated with ALS and it was shown that ATXN2 modifies TDP-43 toxicity. Although ATXN2’s contribution to TDP-43 proteinopathies has been mostly studied in ALS, recent studies have shown that intermediate repeat expansions of ATXN2 also influence the phenotype of FTLD by an unknown mechanism. To address this issue, we immunohistochemically and biochemically analyzed the intracellular dynamics of ATXN2 in brains of normal controls and FTLD-TDP cases. The immunohistochemical studies revealed that ATXN2 localized in the neuronal cytoplasm and proximal dendrites, and expressed widely and uniformly in normal human brains. A semi-quantitative immunofluorescent analysis of normal brains revealed that the cytoplasmic ATXN2 strongly associates with ribosomal protein S6 and poly-A binding protein 1 and partially overlaps with the endoplasmic reticulum marker Calnexin, suggesting a major role of ATXN2 in protein synthesis. The results of immunohistochemical and biochemical analyses of brains from FTLD-TDP cases showed the colocalization of ATXN2 and phosphorylated TDP-43 in the dystrophic neurites and the neuronal cytoplasmic inclusions in the hippocampal region, and a significant reduction of ATXN2 protein compared to controls. These results suggest that ATXN2 is involved in the pathological process of FTLD-TDP. It remains to be clarified whether reduced ATXN2 expression induces neurodegeneration by impairing protein synthesis or plays a neuroprotective role by attenuating the toxicity of TDP-43 aggregates in FTLD-TDP and other TDP-43 proteinopathies.

Highlights

  • Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease (MND), which is characterized by rapidly progressive muscle weakness and paralysis, resulting in death due to respiratory failure within 2–4 years [7]

  • The results showed a strong association of ATXN2 and ribosome in human brains, colocalization of ATXN2 to phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43)-positive aggregates, and the reduced expression of ATXN2 in brains of Frontotemporal lobar degeneration (FTLD)-TDP cases

  • To clarify the role of ATXN2 in the pathogenesis of FTLD-TDP, we examined the intracellular dynamics of ATXN2 in brains of normal controls and FTLD-TDP cases

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Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease (MND), which is characterized by rapidly progressive muscle weakness and paralysis, resulting in death due to respiratory failure within 2–4 years [7]. The affected brain regions sometimes overlap between the two diseases, corresponding with their clinical overlapping. In the brains of the patients with either disease, abnormal intracellular structures consisting of misfolded proteins such as the TAR DNA-binding protein of 43 kDa (TDP-43) and fused-in-sarcoma (FUS) are seen in the surviving neurons and glial cells in affected regions [1, 24, 29]. Some pathogenic gene mutations are known to cause both ALS and FTLD phenotypes [34]. From these overlapping features, the concept of ALSFTLD as a clinical-pathological-genetic continuum has been propounded and currently accepted [40]

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