Title

Targeting Extracellular Cyclophilin A Reduces Neuroinflammation And Extends Survival In A Mouse Model Of Amyotrophic Lateral Sclerosis

Keywords

Amyotrophic lateral sclerosis; Cyclophilin A; Neuroinflammation

Abstract

Neuroinflammationis amajor hallmarkof amyotrophiclateral sclerosis (ALS), whichis currentlyuntreatable. 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.

Publication Date

2-8-2017

Publication Title

Journal of Neuroscience

Volume

37

Issue

6

Number of Pages

1413-1427

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1523/JNEUROSCI.2462-16.2016

Socpus ID

85012005517 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85012005517

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