Fig. 3

The integrated stress response in neurodegenerative disorders. The integrated stress response (ISR) can be initiated upon sensing ER stress. In Multiple Sclerosis (MS), IFNγ is shown to induce ER stress in myelinating oligodendrocytes (OLs) via the phosphorylation of PERK and eIF2α. The main downstream markers identified in lesions of human MS and the MS animal model EAE (experimental autoimmune encephalomyelitis) are CHOP and BiP. EAE studies show that the ISR can be either detrimental for developing oligodendrocytes or cytoprotective for neurons and mature oligodendrocytes. In Alzheimer’s Disease (AD), the formation of amyloid beta (Aβ) plaques and Tau protein aggregates can initiate ISR primarily through PERK and PKR. ISR markers such as p-PERK and p-eIF2α have been found mainly in the frontal cortex and hippocampus. Evidence implicates PERK activation as either neuroprotective by mitigating Aβ- and tau-induced neuronal death (neuron in green) or cytotoxic by promoting tau phosphorylation and aggregation that lead to neuronal damage (neuron in red). In Parkinson’s Disease (PD), α synuclein and Lewy bodies promote the initiation of the ISR via PERK and HRI phosphorylation. ISR markers are commonly found in the affected substantia nigra and dopaminergic neurons. The PERK-ATF4 signaling pathway is relevant in PD. The involvement of ATF4 in the transcription of Parkin (a pro-survival protein) indicates a cytoprotective role (neuron in green). However, excessive ATF4 activity may contribute to neuronal death by promoting the transcription of pro-apoptotic factors such as Trib3 and CHOP (neuron in red). In Amyotrophic Lateral Sclerosis (ALS) motor neurons in the spinal cord are primarily affected. The ISR is activated by protein aggregation, induced mainly by mutations in TDP-43, SOD1, and FUS. The main markers observed in ALS models and human ALS samples are p-eIF2α, ATF4, CHOP, and BiP. The ISR is mostly detrimental in ALS, and the activation of CHOP in ALS models is linked to apoptosis and neurodegeneration (neuron in red). Figure was created in BioRender