The role of ASK1 in selective striatal lesion formation induced by neuronal injury

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. The systemic administration of 3-nitropropionic acid (3-NP) facilitates the development of selected striatal lesions and it remains unclear whether specific neurons are selectively targeted in 3-NP infused striatal degeneration. Although not entirely elucidated, the mechanisms of neurotoxicity induced by 3-NP have been shown to include the exhaustion of adenosine triphosphate, mitochondrial membrane depolarization, dysregulation of intracellular calcium homeostasis, calpain activation, and the release of pro-apoptotic proteins from mitochondria. The present study is to characterize the regulation of BDNF in each cortical and striatal subregion. This study investigates that mild and chronic exposure of mitochondrial toxin can modulate the C1q level both in cortex and striatum via regulation of TGF-beta from astrocyte. Consequently we investigate how the BDNF is dominantly depleted in striatum, and eventually whether striatal lesion is established in involving in ASK1 pathway.The results of the present work show an alteration of ASK1 pathway molecules, TGF-beta, C1q level, and BDNF level as a final standard to striatal degeneration. By ASK1 down-regulation, improvement in each molecules containing behavioral impairment was evaluated in 3NP- infused mice and 3-NP treated primary neuronal cells. We propose the hypothesis that (1) ASK1 overexpression by systemic infusion of 3-NP promotes the formation of selective striatal lesions, and this occurs apart from just ROS generation. (2) ASK1 may differentially regulate C1q secretion level via active TGF-beta in each brain subregion of cortex and striatum, consequently involved in axon degeneration of corticostriatal projection neuron. When brain is mildly and chronically exposed to mitochondrial toxin, presynaptic neuron (in cortical neuron) degrades first, and then postsynaptic neuron of striatal MSN neuron withers as a consequence of it.Consolidating these results, we suggest that the increased ASK1 is linked to regulation of TGF-beta secreted in astrocytes, and differential C1q expression in neurons triggered by TGF-beta leads degradation of cortical projection and depletion of BDNF in striatal neuron in mice brains systemically infused with 3-NP.