Amyotrophic lateral sclerosis (ALS) is an adult-onset paralytic disease characterized by progressive degeneration of upper (cortical) and lower (spinal) motor neurons from motor cortex, brainstem and spinal cord [
1]. Motor neurons serve as important communication links between the brain and voluntary muscles, so the progressive neurological deterioration of motor neurons results in muscular atrophy and ultimately death from respiratory failure within 1–5 years after disease onset [
2]. About 5%–10% of ALS cases are familial and the remaining 90% are sporadic [
3]. Beyond motor neurons, numerous studies also support the roles of astrocyte-mediated toxicity in the onset and progression of ALS [
4‐
6]. Astrocytes are the major glial cell type in the adult central nervous system (CNS), constituting 20%–40% of the human brain [
7,
8]. Despite their abundance, the roles of astrocytes in modulating neurodegeneration are just starting to be uncovered. Astrocytes are highly secretory cells that play diverse roles in supporting neuronal health, such as modulating the blood-brain barrier [
9], regulating synaptogenesis [
10,
11] and neurotransmitter recycling [
12], providing metabolic support to neurons [
13], and regulating CNS inflammatory responses [
14], which have been extensively reviewed previously [
15‐
17]. It has also been well-documented that diseased astrocytes contribute to neuronal defects and death. Healthy neurons co-cultured with ALS astrocytes display neuronal deficits that result in cell death [
6,
18‐
22]. In addition to reduced secretion of neurotrophic factors and metabolites that support neuronal survival and function [
23], the neurotoxic effects are also considered to be mediated by secreted “toxic factors” [
22] such as pro-inflammatory cytokines. ALS astrocytes are known to take on an inflammatory reactive state [
24], which triggers the release of pro-inflammatory cytokines and chemokines that initiate an inflammatory cascade that results in neuronal damage and death [
25]. An increasing body of evidence also suggests contribution of multiple other bioactive molecules to ALS astrocyte-mediated toxicity, such as lipids, metabolites, microRNAs and even extracellular matrix proteins [
24,
26,
27].
Major challenges exist in studies of astrocyte-mediated toxicity, as the components of astrocyte secretome and their changes in disease conditions remain poorly understood. What constitute a healthy astrocyte secretome? How do the secretory profiles of astrocytes change with ALS progression? Do the changes in ALS astrocyte secretome contribute to motor neuron damage and death? In this review, we aim to shed light on some of these questions by summarizing the key findings supporting the relevance of astrocyte secretome with ALS and discuss the efforts made to elucidate components of the astrocyte secretome. Finally, we will discuss if the astrocyte secretome can be exploited for therapeutic intervention for treatment of ALS.