The new therapeutic target : glial assembly

Abstract

Therapeutic strategies for central nervous system (CNS) diseases have traditionally focused on immune modulation, removal of pathogenic proteins, or direct neuroprotection. However, these approaches are often insufficient to halt disease progression in inflammatory and neurodegenerative disorders. Accumulating evidence suggests that disease pathology cannot be fully explained by dysfunction of a single cell type. Recent studies have revealed that astroglia, oligodendroglia, and microglia form a functional network through connexin–mediated intercellular communication, acting as a dynamic cellular assembly that regulates CNS homeostasis and neuroinflammation. In this review, we define this functional network as the “glial assembly” and summarize evidence indicating that its disruption represents a common pathological basis across inflammatory demyelinating and neurodegenerative diseases. Human neuropathological studies, as well as experimental models of multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease, and multiple system atrophy, demonstrate that alterations in connexin–dependent glial interactions critically influence inflammatory amplification, neuronal vulnerability, and pathological protein handling. Importantly, the glia assembly exhibits disease– and stage–specific reorganization rather than uniform failure. Targeting the glia assembly offers a novel therapeutic concept that complements existing immune– and neuron–directed therapies. Modulation or reconstruction of pathological glia assemblies may provide new opportunities for disease modification in currently treatment–resistant CNS disorders.