Parallel Appearance of Polyglutamine and Transactivation-Responsive DNA-Binding Protein 43 and Their Complementary Subcellular Localization in Brains of Patients With Spinocerebellar Ataxia Type 2.

Abstract

Spinocerebellar ataxia type 2 (SCA2) is caused by mutations in the ATXN2 gene in which toxic effects are triggered by expanded polyglutamine repeats within ataxin-2. SCA2 is accompanied by motor neuron degeneration as occurs in amyotrophic lateral sclerosis (ALS). We investigated the distribution patterns of ataxin-2 and transactivation-responsive DNA-binding protein 43 (TDP-43), a major disease-related protein in ALS, in the CNS of 3 SCA2 patients. Phosphorylated TDP-43 (pTDP-43)-positive lesions were widely distributed throughout the CNS and generally overlapped with 1C2 (expanded polyglutamine)-immunoreactive lesions. This distribution pattern is different from the pattern in limbic-predominant age-related TDP-43 encephalopathy. In SCA2, double immunostaining of TDP-43 and 1C2 in motor neurons revealed 3 staining patterns: cytoplasmic 1C2 and nuclear TDP-43, nucleocytoplasmic 1C2 and nuclear TDP-43, and nuclear 1C2 and cytoplasmic TDP-43, which reflect the early, active, and final stages of pathological change, respectively. The translocation of TDP-43 from the nucleus to the cytoplasm along with the translocation of 1C2 in the opposite direction indicates that nuclear accumulation of the disease-specific protein ataxin-2 affects the intracellular dynamics of TDP-43. Such a close interrelationship between mutant ataxin-2 and TDP-43 in the cell might account for the similarity of their distribution in the CNS of patients with SCA2.

• Authors: Shigeru Koyano, Saburo Yagishita, Mikiko Tada, Hiroshi Doi, Toshiki Uchihara, Fumiaki Tanaka
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 81 Issue 7 Pg. 535-544 (06 20 2022) ISSN: 1554-6578 [Electronic] England
• PMID: 35511239 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 American Association of Neuropathologists, Inc. All rights reserved.

Chemical References

• Ataxin-2
• DNA-Binding Proteins
• Peptides
• TARDBP protein, human
• polyglutamine

Topics

• Ataxin-2 (genetics, metabolism)
• Brain (pathology)
• DNA-Binding Proteins (genetics, metabolism)
• Humans
• Peptides
• Spinocerebellar Ataxias (genetics, pathology)
• Transcriptional Activation (genetics)