UPR activation in ALS human samples and mouse models of the disease. Several examples of published data indicating the activation of the UPR in SALS human samples and animal models. (a) Immunostaining of spinal cord motoneurons with the neurofilament marker SMI-32 showing PDIA1 (PDI) overexpression in samples from two sporadic ALS patients (sALS) compared with healthy subjects. Scale bar, 10 μm (from Atkin et al. [30]). (b) Immunohistochemistry of spinal cord section from a familial ALS patient (fALS) with a FUS mutation. The colocalization of FUS protein (left panel) and PDIA1 (PDI) protein (right panel) is indicated with black arrows. Scale bar, 40 μm (from Farg et al. [92]). (c) Left panel, immunodetection of the UPR sensor ATF6 (green), neurofilament (NF-H, red), and DAPI (blue) in spinal cord sections from mutant mice and nontransgenic control animals (NTG). Scale bar, 20 μm. Right panel, SOD1 protein detection in ER lumen by immunoelectron microscopy in mutant, SOD1 wild-type , and nontransgenic (NTG) mice. Scale bar, 50 nm (from Kikuchi et al. [38]). (d) Left panel, CHOP positive cells detected in spinal cord sections from human sporadic ALS (sALS) patient. Control tissue in (A), (C), and (E). Pictures derived from cervical spinal cord ((A) and (B)), thoracic spinal cord ((C) and (D)), and lumbar spinal cord ((E) and (F)). Scale bars, 65 μm. In the right panel, immunolocalization of CHOP (green) in anti-ChAT (red) positive spinal cord motoneurons from mutant mice. Scale bar: 40 μm. The areas with a box are shown at higher magnification. Scale bar 10 μm (from Ito et al. [33]). (e) Immunostaining of corticospinal motor neurons from 3-month-old transgenic mice. Transgene detected with GFP (green), PDIA1 (PDI) (red staining), and VAPB (blue staining). Arrowheads show neurons with accumulation of PDI and VAPB. Scale bar: 20 μm (from Aliaga et al. [50]). Copyright authorization was obtained from each journal for all images.
