Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by selective death of motor neurons in the cortex, brainstem, and spinal cord. Cytosolic phospholipase A2 alpha (cPLA2α) upregulation and activation in the spinal cord of patients with sporadic ALS and in the spinal cord of human mutant SOD1G93A (hmSOD1) transgenic mice were recently reported.MethodscPLA2α upregulation in the brainstem and spinal cord was reduced by brain infusion of a specific antisense oligonucleotide against cPLA2α (AS), and the effect was evaluated on disease progression and brain cell activation.ResultsWe found that the elevation of cPLA2α protein expression in the spinal cord was first detected at 6-week-old hmSOD1 mice and remained elevated during their whole life span. Reduction of the elevated expression of cPLA2α in the spinal cord of hmSOD1 mice by brain infusion of an AS at week 15 (shortly before the appearance of the disease symptoms), for a duration of 6 weeks, delayed the loss of motor neuron function in comparison with hmSOD1 mice and with sense brain-infused hmSOD1 mice. To characterize the effect of cPLA2α upregulation on different processes taking place at the appearance of the disease symptoms, mice were brain infused with AS or with sense at week 15 for 3–4 weeks. The AS treatment that reduced cPLA2α upregulation in the spinal cord of AS-treated hmSOD1 mice (as analyzed at week 18–19) prevented the reduction in the number of the neurons (detected by NeuN) and inhibited astrocyte activation (detected by GFAP) and microglia activation (detected by Iba-1 and by CD40). In addition, AS treatment blunted the upregulation of the proinflammatory enzyme-inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) detected in hmSOD1 mice.ConclusionsSince specific reduction of cPLA2α in the brainstem and spinal cord significantly attenuated the development of the disease, cPLA2α may offer an efficient target for treatment of ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by selective death of motor neurons in the cortex, brainstem, and spinal cord
The present study aims to determine whether the elevation of cytosolic phospholipase A2α (cPLA2α) protein expression in the spinal cord and brainstem has a role in the pathogenesis of the disease, using a mouse model of human mutant SOD1G93A (hmSOD1) mice
In order to study the role of cPLA2α in the development of ALS, cPLA2α protein expression was analyzed in the spinal cord of hmSOD1 mice (Fig. 1a) at different stages during their life span (Fig. 1b)
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by selective death of motor neurons in the cortex, brainstem, and spinal cord. Amyotrophic lateral sclerosis (ALS) is a severe degenerative disorder, mainly affecting the motor neurons in the spinal cord, brainstem, and cortex. ALS is not primarily considered an inflammatory or immune-mediated disease, immune mechanisms appear to play a role in the pathogenesis of the disease. In both ALS patients and animal models, inflammatory responses have been observed [3,4,5]. Selective ablation of mutant SOD1 in astrocytes and microglial cells by conditional deletion [8] and neonatal wild-type bone marrow transplantation [6] increased motor neuron survival and life span. It has been reported that in the CNS, natural killer cells and peripheral T cells infiltrate the spinal cord [9]
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