Amyotrophic lateral sclerosis (ALS) is the most frequent paralytic disease in adults. Most ALS cases are considered sporadic with no clear genetic component. The disruption of protein homeostasis due to chronic stress responses at the endoplasmic reticulum (ER) and the accumulation of abnormal protein inclusions are extensively described in ALS mouse models and patient-derived tissue. Recent studies using pharmacological and genetic manipulation of the unfolded protein response (UPR), an adaptive reaction against ER stress, have demonstrated a complex involvement of the pathway in experimental models of ALS. In addition, quantitative changes in ER stress-responsive chaperones in body fluids have been proposed as possible biomarkers to monitor the disease progression. Here we review most recent advances attributing a causal role of ER stress in ALS. 1. Introduction Several neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS), share common features, among them the presence of abnormal protein aggregates and the inclusions containing specific misfolded proteins. The presence of these abnormal protein aggregates has been temporally and spatially correlated with the activation of stress signaling pathway emerging from the endoplasmic reticulum (ER), a cellular reaction named the “unfolded protein response” (UPR). In the last years, ER stress levels and UPR activation in neurodegenerative diseases have been extensively studied. In this review, we focus on recent findings placing ER stress as a key component of neurodegeneration in ALS and discuss the different mechanisms by which the UPR may impact disease progression and the therapeutic potential of manipulating this signaling pathway in ALS. 2. Amyotrophic Lateral Sclerosis ALS is a progressive and deadly adult-onset motoneuron disease characterized by muscle weakness, spasticity, atrophy, paralysis, and premature death [1, 2]. The pathological hallmark of ALS is the selective degeneration of motoneurons in the spinal ventral horn, most of brainstem nuclei, and cerebral cortex. ALS has an average age of onset around 50 years and estimated incidence of 1-2 cases per 100,000 individuals [1]. ALS is presently incurable with a mean survival time of 1–5 years from diagnosis, often resulting in fatal respiratory dysfunction. The majority of ALS patients lack a defined hereditary genetic component and are considered sporadic (sALS), while approximately 10% of cases are familial (fALS) [1]. The most common genetic causes of
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