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Updated: Sep 24, 2025
Cerebellar Regional Dissection for Molecular Analysis
Published on: December 5, 2020
Parallel Appearance of Polyglutamine and Transactivation-Responsive DNA-Binding Protein 43 and Their Complementary
Shigeru Koyano1,2,3, Saburo Yagishita1,2, Mikiko Tada1
1Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
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.
Insights
Spinocerebellar ataxia type 2 (SCA2) involves mutations in the ATXN2 gene, leading to motor neuron degeneration. This study reveals overlapping distribution patterns of mutant ataxin-2 and TDP-43 in the central nervous system of SCA2 patients, suggesting a close interrelationship.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by ATXN2 gene mutations with expanded polyglutamine repeats.
- SCA2 shares motor neuron degeneration characteristics with amyotrophic lateral sclerosis (ALS).
- Transactivation-responsive DNA-binding protein 43 (TDP-43) is a key protein implicated in ALS pathogenesis.
Purpose of the Study:
- To investigate the distribution patterns of ataxin-2 and TDP-43 in the central nervous system (CNS) of SCA2 patients.
- To explore the relationship between mutant ataxin-2 and TDP-43 pathology in SCA2.
- To understand the cellular dynamics and disease stages reflected by protein distribution.
Main Methods:
- Human CNS tissue analysis from 3 SCA2 patients.
- Immunohistochemistry using 1C2 antibody for expanded polyglutamine (ataxin-2) and antibodies for TDP-43.
- Double immunostaining to examine co-localization and cellular localization of ataxin-2 and TDP-43 in motor neurons.
Main Results:
- Phosphorylated TDP-43 (pTDP-43) positive lesions were widespread in the CNS of SCA2 patients, overlapping with expanded polyglutamine (1C2) lesions.
- The distribution pattern of pTDP-43 in SCA2 differs from that observed in limbic-predominant age-related TDP-43 encephalopathy.
- Three distinct TDP-43 and 1C2 staining patterns in motor neurons indicated different stages of pathological progression, with evidence of nucleocytoplasmic shuttling.
Conclusions:
- Mutant ataxin-2 accumulation influences TDP-43 intracellular dynamics, causing its translocation from the nucleus to the cytoplasm.
- The observed interrelationship and overlapping distribution of mutant ataxin-2 and TDP-43 in the CNS of SCA2 patients likely contribute to the disease's pathology.
- These findings highlight a shared pathomechanism between SCA2 and ALS involving TDP-43 dysfunction.
