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

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.

The integrated stress response in brain diseases: A double-edged sword for proteostasis and synapses.

The integrated stress response (ISR) is a highly conserved biochemical pathway that regulates protein synthesis. The ISR is activated in response to diverse stressors to restore cellular homeostasis. As such, the ISR is implicated in a wide range of diseases, including brain disorders.

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

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 in the process of synaptic plasticity, which is a substrate for adaptive behavior.

The Perineuronal Net Protein Brevican Acts in Nucleus Accumbens Parvalbumin-Expressing Interneurons of Adult Mice to Regulate Excitatory Synaptic Inputs and Motivated Behaviors.

Background: Experience-dependent functional adaptation of nucleus accumbens (NAc) circuitry underlies the development and expression of reward-motivated behaviors. Parvalbumin-expressing GABAergic (gamma-aminobutyric acidergic) interneurons (PVINs) within the NAc are required for this process. Perineuronal nets (PNNs) are extracellular matrix structures enriched around PVINs that arise during development and have been proposed to mediate brain circuit stability.