Protective Role of Glial Heat Shock Proteins in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease in which multiple cell types and cellular pathways play a role. A pathological hallmark of neurodegenerative disorders, including ALS, is the presence of intracellular aggregates. Heat Shock Proteins (Hsp) are a family of protein chaperones that normally play a key role in protein homeostasis, acting to prevent aggregation of misfolded proteins. In ALS, Hsp are sequestered into aggregates, creating a cytosolic deficit in Hsp availability and function, thereby reducing their ability to respond to cell stress and prevent aggregation of misfolded proteins. Furthermore, not only is the neuronal support normally provided by surrounding glial cells lost ALS, but glia actively contribute towards motor neuron degeneration. Here, we discuss the possibility that dysfunction of Hsp in glia may contribute to non-cell autonomous mechanisms of motor neuron death in ALS, for example by exacerbating inflammatory signalling in glia. Since motor neurons are unable to upregulate Hsp in response to stress, it is possible they rely on surrounding glia to provide them with Hsp, and this support may be lost in ALS. Therefore, therapeutic approaches that augment Hsp levels may have neuroprotective effects on motor neurons and may correct ALS-induced deficits in glia.