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Apoptosis signal-regulating kinase-1 aggravates ROS-mediated striatal degeneration in 3-nitropropionic acid-infused
Kyoung Joo Cho1, Hyun Woo Kim, So Yeong Cheon
1Department of Neurology, College of Medicine, Yonsei University, Republic of Korea; Department of Anatomy and Brain Korea 21 Project for Medical Science, Yonsei University, College of Medicine, Seoul 120-752, Republic of Korea.
Abstract:
Apoptosis signal-regulating kinase-1 (ASK1), an early signaling element in the cell death pathway, has been suggested to participate in the pathology of neurodegenerative diseases, which may be associated with environmental factors that impact the diseases. Although it is not entirely elucidated, 3-nitropropionic acid (3-NP) provokes mitochondrial dysfunction and selectively forms striatal lesions similar to those found in Huntington's disease. The current study investigated whether ASK1 is involved in striatal pathology following chronic systemic infusion of 3-NP. The results show that ASK1 acts as a primary mediator of there active oxygen species (ROS) cell death signal cascade in the 3-NP-damaged striatal region by disrupting the positive feedback cycle. In 3-NP-infused striatal lesions, ROS increased ASK1. Superoxide dismutase transgenic (SOD-tg) mice reduced ASK1by scavenging ROS, and reduction of ASK1leads to a reduction in cell death. However, ASK1 down-regulation in 3-NP infusion mice also decreased striatal cell death without scavenging ROS. In contrast decreasing cell death by si-ASK1 treatment along with 3-NP in both SOD tg and wild-type mice (wt), cell death rebounded when ASK1 peptide was added to SOD tg mice. The present study suggests that ROS-inducing ASK1 may be an important step in the pathogenesis of 3-NP infused striatal lesions in murine brains.
Insights
Apoptosis signal-regulating kinase-1 (ASK1) mediates cell death in 3-nitropropionic acid (3-NP) induced striatal lesions. Reducing ASK1 in mice lessens neurodegeneration, suggesting ASK1 as a therapeutic target for Huntington's disease-like conditions.
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Apoptosis signal-regulating kinase-1 (ASK1) is implicated in neurodegenerative disease pathology.
- 3-nitropropionic acid (3-NP) induces striatal lesions and mitochondrial dysfunction, mimicking Huntington's disease.
- Environmental factors may influence neurodegeneration linked to ASK1 signaling.
Purpose of the Study:
- To investigate the role of ASK1 in striatal pathology induced by chronic 3-NP infusion.
- To determine if ASK1 mediates reactive oxygen species (ROS) signaling in 3-NP-damaged striata.
- To explore the therapeutic potential of targeting ASK1 in 3-NP-induced neurodegeneration.
Main Methods:
- Chronic systemic infusion of 3-NP in wild-type and superoxide dismutase transgenic (SOD-tg) mice.
- Assessment of ASK1 and ROS levels in striatal lesions.
- Intervention with si-ASK1 treatment and ASK1 peptide administration.
- Evaluation of cell death markers in response to treatments.
Main Results:
- 3-NP infusion increased ASK1 and ROS in striatal lesions.
- ROS scavenging in SOD-tg mice reduced ASK1 and subsequent cell death.
- ASK1 down-regulation, via si-ASK1, decreased striatal cell death independently of ROS scavenging.
- ASK1 inhibition blocked cell death, while its addition in SOD-tg mice caused cell death rebound.
Conclusions:
- ASK1 acts as a key mediator in the ROS-induced cell death pathway within 3-NP-damaged striata.
- Targeting ASK1 significantly reduces cell death in 3-NP-induced striatal lesions.
- ASK1 is a critical factor in the pathogenesis of 3-NP-induced neurodegeneration, offering a potential therapeutic target.
