Severe neonatal onset neuroregression with paroxysmal dystonia and apnoea: Expanding the phenotypic and genotypic spectrum of <i>CARS2</i>‐related mitochondrial disease

Advances in genetic technologies and disease modeling have greatly accelerated the pace of introducing and validating molecular‐genetic contributors to disease. In dystonia, there is a growing convergence across multiple distinct forms of the disease onto core biological processes. Here, we discuss two of these, the endosome‐autophagosome‐lysosome pathway and the integrated stress response, to highlight recent advances in the field. Using these two pathomechanisms as examples, we further discuss the opportunities that molecular‐genetic grouping of dystonias present to transform dystonia care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia

Calakos,

Caffall

2024

Journal of Clinical Investigation

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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.

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Severe neonatal onset neuroregression with paroxysmal dystonia and apnoea: Expanding the phenotypic and genotypic spectrum of CARS2‐related mitochondrial disease

Cited by 3 publications

References 22 publications

Severe neonatal onset neuroregression with paroxysmal dystonia and apnoea: Expanding the phenotypic and genotypic spectrum of CARS2‐related mitochondrial disease

Severe neonatal onset neuroregression with paroxysmal dystonia and apnoea: Expanding the phenotypic and genotypic spectrum of CARS2‐related mitochondrial disease

Emerging Molecular‐Genetic Families in Dystonia: Endosome‐Autophagosome‐Lysosome and Integrated Stress Response Pathways

The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia

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