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

Abstract

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.

Keywords: autophagy; endosomal trafficking; dystonia; eIF2 α; Eif2s1; HOPS complex; integrated stress response; ISR; lysosome..

FIG. 1

Schematic of genes associated with dystonia and endosome‐autophagosome‐lysosome function overlaid onto potential relevant biological processes. Endosomal vesicle trafficking, autophagosome formation, and fusion with the lysosomes are illustrated. Endocytosis is depicted in the upper left corner. The endosomal system selects molecules for recycling via the trans‐golgi network (TGN) or lysosomal degradation. The endoplasmic reticulum (ER) is involved in autophagy induction (upper right corner). Mitophagy and ferritinophagy, specific autophagic clearance processes required for degradation of mitochondria and ferritin, respectively, are also shown. Fusion of autophagosomes and late endosomes with lysosomes is essentially mediated by the assistance of the homotypic fusion and vacuole protein sorting (HOPS) complex, a highly conserved functional tether consisting of vacuolar protein sorting (Vps) proteins (black box). Following fusion, target molecules are degraded via lysosomal hydrolases. Dystonia‐related genes and products affecting various stages of the endosome‐autophagosome‐lysosome pathway (EALP) are highlighted, alongside the mechanism(s) to which they are functionally linked. EALP impairments are likely to impact neurodevelopment and neuronal survival. The figure is a modification of previous illustrations of HOPS‐complex defects in dystonia, and was created with Biorender.com. Brain‐2 icon by Servier https://smart.servier.com/ is licensed under CC‐BY 3.0 Unported https://creativecommons.org/licenses/by/3.0/. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 2

Schematic of genes associated with dystonia and the integrated stress response (ISR) overlaid onto potential relevant biological processes. Summary diagram illustrating cellular components, biological processes and dystonia‐associated genes that intersect the function of the ISR pathway. Several regulators function in the activation of the ISR and the ISR impacts many downstream effector cascades including translational control. Dystonia‐associated genes are highlighted in light pink. NPC, nuclear pore complex; ER, endoplasmic reticulum; ROS, reactive oxygen species. Brain‐2, mitochondrium‐1, DNA‐nucleotides, endoplasmatic‐reticulum‐medium, and golgi‐2d‐1 icons by Servier https://smart.servier.com/ is licensed under CC‐BY 3.0 Unported https://creativecommons.org/licenses/by/3.0/. Interneuron, Nuclear_pore_complex, and Motor_neuron icons by DBCLS https://togotv.dbcls.jp/en/pics.html is licensed under CC‐BY 4.0 Unported https://creativecommons.org/licenses/by/4.0/. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 3

Schematic highlighting potential mechanistic intersections and targeted therapeutics for endosome‐autophagosome‐lysosome pathway (EALP) and integrated stress response (ISR) disorders. Potential points of targeted treatment are displayed, with interventions in the stress‐response, lysosomal, and mitochondrial pathways highlighted. Examples of dystonia‐associated biological processes that intersect are indicated by black arrows. [Color figure can be viewed at wileyonlinelibrary.com]