A wide range of pathological conditions can affect normal functioning of the nervous system, from neurodevelopmental problems to neurodegenerative diseases, constituting the second leading cause of death and the major factor for disability worldwide. The etiology of neurological disorders is varied and complex, including genetic mutations, trauma, viral infections, aging, and many others. Most of these pathologies are incurable, meaning an urgent need for novel therapeutic strategies to improve neural activity and halt neuronal loss to be developed. Perturbations to proteostasis of the nervous system have emerged as important pathogenic mechanisms contributing to protein aggregation, synaptic failure, neuroinflammation, among other disease hallmarks. The complex interplay between proteostasis regulation and myriad cellular functions offers multiples point of intervention to be exploited therapeutically.
The endoplasmic reticulum (ER) is an organelle involved in synthesis and folding of membrane and secretory proteins that exerts a critical role in the nervous system, dictating patterns of cell migration and differentiation during development, in addition to contributing to the maintenance and remodeling of the intricate neuronal morphology and synaptic activity. Studies in patients and experimental models established that ER proteostasis is compromised across several conditions, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, psychiatric disorders, intellectual disability and neuropathic pain. The proteostasis network in the ER has many components such as chaperones and folding catalysts, degradation systems based on proteasomal and lysosomal pathways and the unfolded protein response that are disrupted in neurological disorders. Moreover, ER proteostasis also relies on the structural and functional integration of the ER with other organelles such as the mitochondria and redox platforms, in addition to being modulated by lipid metabolism. The growing mechanistic understanding of how these cellular systems are involved in the etiology of these conditions provides the conceptual framework for the design of multimodal pharmacological interventions. Basic and translational research should advance in parallel to identify and explore therapeutic targets through a discovery pipeline supported by human genetics, development of pre-clinical models and drug screenings.
This Research Topic aims to gather original research, brief research reports, systematic reviews, reviews, mini reviews and perspectives on recent progress towards elucidation of pathogenic mechanisms, proof-of-concept studies for therapeutic targets and drug development and repositioning that describe or exploit the potential of restoring ER proteostasis to treat neurological disorders. Potential subjects include but are not limited to the following themes:
1) Human genetic studies reporting novel variants causing neurological disorders.
2) Neurodevelopmental determinants of pathological aging.
3) Cell autonomous and non-cell autonomous disease mechanisms.
4) Neuro-immune crosstalk and neuroinflammation.
5) Communication between ER and other organelles.
6) Redox signaling and regulation of proteostasis.
7) Integration of ER proteostasis with lipid metabolism.
8) Identification of therapeutic targets and rational drug design.
9) Drug screening of natural sources and synthetic libraries.
10) Drug repositioning.
11) Gene therapy development.
12) Use of animal models in pre-clinical studies.
Important note: manuscripts reporting crude extracts and complex mixtures without clear mechanism of action, in addition to drug screenings relying solely on bioinformatics, are out of scope of the present Research Topic.
A wide range of pathological conditions can affect normal functioning of the nervous system, from neurodevelopmental problems to neurodegenerative diseases, constituting the second leading cause of death and the major factor for disability worldwide. The etiology of neurological disorders is varied and complex, including genetic mutations, trauma, viral infections, aging, and many others. Most of these pathologies are incurable, meaning an urgent need for novel therapeutic strategies to improve neural activity and halt neuronal loss to be developed. Perturbations to proteostasis of the nervous system have emerged as important pathogenic mechanisms contributing to protein aggregation, synaptic failure, neuroinflammation, among other disease hallmarks. The complex interplay between proteostasis regulation and myriad cellular functions offers multiples point of intervention to be exploited therapeutically.
The endoplasmic reticulum (ER) is an organelle involved in synthesis and folding of membrane and secretory proteins that exerts a critical role in the nervous system, dictating patterns of cell migration and differentiation during development, in addition to contributing to the maintenance and remodeling of the intricate neuronal morphology and synaptic activity. Studies in patients and experimental models established that ER proteostasis is compromised across several conditions, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, psychiatric disorders, intellectual disability and neuropathic pain. The proteostasis network in the ER has many components such as chaperones and folding catalysts, degradation systems based on proteasomal and lysosomal pathways and the unfolded protein response that are disrupted in neurological disorders. Moreover, ER proteostasis also relies on the structural and functional integration of the ER with other organelles such as the mitochondria and redox platforms, in addition to being modulated by lipid metabolism. The growing mechanistic understanding of how these cellular systems are involved in the etiology of these conditions provides the conceptual framework for the design of multimodal pharmacological interventions. Basic and translational research should advance in parallel to identify and explore therapeutic targets through a discovery pipeline supported by human genetics, development of pre-clinical models and drug screenings.
This Research Topic aims to gather original research, brief research reports, systematic reviews, reviews, mini reviews and perspectives on recent progress towards elucidation of pathogenic mechanisms, proof-of-concept studies for therapeutic targets and drug development and repositioning that describe or exploit the potential of restoring ER proteostasis to treat neurological disorders. Potential subjects include but are not limited to the following themes:
1) Human genetic studies reporting novel variants causing neurological disorders.
2) Neurodevelopmental determinants of pathological aging.
3) Cell autonomous and non-cell autonomous disease mechanisms.
4) Neuro-immune crosstalk and neuroinflammation.
5) Communication between ER and other organelles.
6) Redox signaling and regulation of proteostasis.
7) Integration of ER proteostasis with lipid metabolism.
8) Identification of therapeutic targets and rational drug design.
9) Drug screening of natural sources and synthetic libraries.
10) Drug repositioning.
11) Gene therapy development.
12) Use of animal models in pre-clinical studies.
Important note: manuscripts reporting crude extracts and complex mixtures without clear mechanism of action, in addition to drug screenings relying solely on bioinformatics, are out of scope of the present Research Topic.