ABSTRACT
Neuroinflammation is a major hallmark of amyotrophic lateral sclerosis (ALS), which is currently untreatable. Several anti-inflammatory compounds have been evaluated in patients and in animal models of ALS, but have been proven disappointing in part because effective targets have not yet been identified. Cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), as a foldase is beneficial intracellularly, but extracellularly has detrimental functions. We found that extracellular PPIA is a mediator of neuroinflammation in ALS. It is a major inducer of matrix metalloproteinase 9 and is selectively toxic for motor neurons. High levels of PPIA were found in the CSF of SOD1G93A mice and rats and sporadic ALS patients, suggesting that our findings may be relevant for familial and sporadic cases. A specific inhibitor of extracellular PPIA, MM218, given at symptom onset, rescued motor neurons and extended survival in the SOD1G93A mouse model of familial ALS by 11 d. The treatment resulted in the polarization of glia toward a prohealing phenotype associated with reduced NF-κB activation, proinflammatory markers, endoplasmic reticulum stress, and insoluble phosphorylated TDP-43. Our results indicates that extracellular PPIA is a promising druggable target for ALS and support further studies to develop a therapy to arrest or slow the progression of the disease in patients.SIGNIFICANCE STATEMENT We provide evidence that extracellular cyclophilin A, also known as peptidylprolyl cis-/trans-isomerase A (PPIA), is a mediator of the neuroinflammatory reaction in amyotrophic lateral sclerosis (ALS) and is toxic for motor neurons. Supporting this, a specific extracellular PPIA inhibitor reduced neuroinflammation, rescued motor neurons, and extended survival in the SOD1G93A mouse model of familial ALS. Our findings suggest selective pharmacological inhibition of extracellular PPIA as a novel therapeutic strategy, not only for SOD1-linked ALS, but possibly also for sporadic ALS. This approach aims to address the neuroinflammatory reaction that is a major hallmark of ALS. However, given the complexity of the disease, a combination of therapeutic approaches may be necessary.
Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Cyclophilin A/metabolism , Disease Models, Animal , Extracellular Fluid/metabolism , Inflammation Mediators/metabolism , Adult , Aged , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/mortality , Animals , Cell Survival/drug effects , Cell Survival/physiology , Cells, Cultured , Coculture Techniques , Cyclophilin A/antagonists & inhibitors , Drug Delivery Systems/methods , Enzyme Inhibitors/administration & dosage , Extracellular Fluid/drug effects , Female , Humans , Inflammation/drug therapy , Inflammation/metabolism , Inflammation Mediators/antagonists & inhibitors , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Neurons/drug effects , Neurons/metabolism , Survival Rate/trendsABSTRACT
Using paired pulse transcranial magnetic stimulation (TMS) paradigms, we studied cortical excitability in a patient with spinal cord lesion. During posterior tibial nerve stimulation, the contextual flexion of hand fingers contralateral to the stimulated lower limb had suggested a change in motor cortex excitability. Results showed a decrease in the activity of motor cortex inhibitory circuits. This could suggest that in spinal cord injury, just as in stroke and peripheral deafferentation, a disinhibition of latent synapses within the motor cortex and the rewriting of a new motor map can occur.
