Abstract
Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38. ASK1 may be activated by a variety of extracellular and intracellular stimuli. MAP kinase activation in the sensory nervous system as a result of diabetes has been shown in numerous preclinical and clinical studies. As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy. We therefore wanted to characterize the expression of ASK1 in sensory neurons, and determine whether the absence of functional ASK1 would protect against the development of neuropathy in a mouse model of experimental diabetes. ASK1 mRNA and protein is constitutively expressed by multiple populations of sensory neurons of the adult mouse lumbar DRG. Diabetes was induced in male C57BL/6 and transgenic ASK1 kinase-inactive (ASK1n) mice using streptozotocin. Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes. However, levels of ASK2 mRNA increase in the spinal cord at 4 weeks of diabetes, which could represent a future target for this field. Neither motor nerve conduction velocity deficits, nor thermal or mechanical hypoalgesia were prevented or ameliorated in diabetic ASK1n mice. These results suggest that activation of ASK1 is not responsible for the nerve deficits observed in this mouse model of diabetic neuropathy.
Highlights
A number of apoptosis-signalling kinase species have been identified: Apoptosis signal-regulating kinase-1 (ASK1) [1], ASK2 [2] and ASK3 [3]
Western blots probed for pp38, tp38 and ERK (i) of sciatic nerve (D) and spinal cord (E) from 12-week C57 and ASK1 kinase-inactive (ASK1n) diabetic and control mice, with densitometric analysis of pp38 (ii) and tp38 (iii) relative to ERK1, confirmed that p38 activation is unchanged in nerve tissue from 12-week diabetic mice, and that overall, p38 activation is significantly reduced in ASK1n mice compared with C57 mice (p,0.05 in sciatic nerve; p,0.01 in spinal cord overall in a 2-way ANOVA; *p,0.05 in Bonferroni post hoc tests, n = 5–6)
Increased p38 mitogen-activated protein (MAP) kinase activation has been implicated in the etiology of a variety of behavioural and electrophysiological indices of diabetic neuropathy [25]
Summary
A number of apoptosis-signalling kinase species have been identified: ASK1 [1], ASK2 [2] and ASK3 [3]. As their name suggests, activation of these mitogen-activated protein (MAP) 3 kinases can trigger apoptosis of the cell in response to cellular stress, for example: oxidative stress, tumour necrosis factor-a (TNF-a) and Fas antigen activation, all of which may be induced by disease [3]. Given the highly regulated nature of ASK1, its activity is tightly controlled by a number of regulatory molecules able to bind and phosphorylate ASK1 at specific sites [7,8,9]. Dissociation of thioredoxin is required for ASK1 activation [12]
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