The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia
Nicole Calakos, Zachary F. Caffall
Nicole Calakos, Zachary F. Caffall
Published April 1, 2024
Citation Information: J Clin Invest. 2024;134(7):e177833. https://doi.org/10.1172/JCI177833.
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The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia

Abstract

The integrated stress response (ISR) is a highly conserved biochemical pathway involved in maintaining proteostasis and cell health in the face of diverse stressors. In this Review, we discuss a relatively noncanonical role for the ISR in neuromodulatory neurons and its implications for synaptic plasticity, learning, and memory. Beyond its roles in stress response, the ISR has been extensively studied in the brain, where it potently influences learning and memory, and the process of synaptic plasticity, which is a substrate for adaptive behavior. Recent findings demonstrate that some neuromodulatory neuron types engage the ISR in an “always-on” mode, rather than the more canonical “on-demand” response to transient perturbations. Atypical demand for the ISR in neuromodulatory neurons introduces an additional mechanism to consider when investigating ISR effects on synaptic plasticity, learning, and memory. This basic science discovery emerged from a consideration of how the ISR might be contributing to human disease. To highlight how, in scientific discovery, the route from starting point to outcomes can often be circuitous and full of surprise, we begin by describing our group’s initial introduction to the ISR, which arose from a desire to understand causes for a rare movement disorder, dystonia. Ultimately, the unexpected connection led to a deeper understanding of its fundamental role in the biology of neuromodulatory neurons, learning, and memory.

Authors

Nicole Calakos, Zachary F. Caffall

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Figure 3

Dystonia-associated mutations in genes influencing the activation and outcome of the ISR.

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Dystonia-associated mutations in genes influencing the activation and ou...
A summary of the ISR pathway’s relationship to key components of translational initiation highlights intersections with proteins encoded by genes harboring mutations associated with clinical phenotypes of dystonia. Functional evidence supports ISR involvement in multiple monogenic forms of dystonia and dystonia/Parkinsonism (PRKRA [refs. 21, 22, 94], TOR1A [refs. 5, 29], THAP1 [ref. 32]). Human genes associated with effects on the ISR, or translational initiation, that present with clinical phenotypes of dystonia include PKR (EIF2AK2) (23–27), EIF2B (42, 95), ATF4 (5), EIF4A2 (28), and a range of tRNA synthetase genes associated with mitochondrial disorders (33–41) (e.g., AARS1, AARS2, CARS2, EARS2, WARS2, TARS2). Activation of the ISR results in phosphorylation of the α subunit of eIF2 and reduces the rate of eIF2B-mediated GDP/GTP exchange of eIF2, preventing the formation of the ternary complex (TC) (GTP-eIF2-Met tRNA). Reduction in TC abundance limits the rate of elongation reinitiation following regulatory upstream open reading frames (uORFs) by slowing the rate of preinitiation complex (PIC; “43S”) formation (6, 7, 9). This delay in reinitiation following a regulatory uORF results in translational reprogramming based on mRNA uORF structure. ATF4 is preferentially translated under these conditions and is the best-characterized effector of ISR pathway activation. As it is the obligate guanine exchange factor for eIF2, formation of the TC is dependent on eIF2B function. EIF4A modifies mRNA secondary structure to enhance small ribosomal subunit (40S) mRNA scanning (96). Additionally, mutations in tRNA synthetase genes are known to chronically activate the ISR through stimulation of GCN2 (97) and may additionally delay translational initiation by limiting the availability of charged tRNAs.