Upregulating CD59: a new strategy for protection of neurons from complement-mediated degeneration

Abstract

An increasing number of studies have shown a critical role for the membrane attack complex, synthesized on activation of the terminal pathway of the complement system, in causing demyelination and neuronal death in neurodegeneration. The aim of this study was to develop a strategy to increase the resistance of neurons to complement damage by modulating the expression of membrane complement regulatory protein CD59, the only inhibitor of the terminal pathway of the complement cascade. We exploited our recent finding that CD59 expression is regulated by the neural-restrictive silencer factor (REST) and designed a novel REST-derived peptide (REST5) containing the nuclear localization domain of the wild-type protein. The effect of REST5 and the mechanism by which it modulates CD59 expression were modelled in neuroblastoma cells transfected with expression constructs, and then confirmed in human neurons differentiated from neural progenitor cells. REST5 increased the expression of CD59 in neurons by fivefold and protected them from complement-mediated lysis spontaneously triggered by neurons. As a source of complement, we used either human serum or conditioned medium from primary human oligodendroglia. This study brings new insight into immunopharmacological research that may serve to inhibit neuronal death triggered by the terminal pathway of complement activation.

Membrane attack complex inhibitor CD59a protects against focal cerebral ischemia in mice

“…The ongoing debate of whether the complement system is 'friend or foe' in ischemic brain injury [60] may be explained by the complexity of the system and the manifold pathways which are activated by the complement system, and the different ways complement may be inhibited at different levels of the complement cascade. Thus, our data which demonstrates model- and gender-specific effects of MAC-inhibition by CD59a, replenishes the current understanding of the complement system in ischemic brain injury and thus may contribute to the development of future therapeutical strategies [61]. …”

What does complement do in Alzheimer’s disease? Old molecules with new insights

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