Serotonergic Dysfunction and the Interacting Role of TAR DNA-Binding Protein 43 in the Progression of Amyotrophic Lateral Sclerosis: A Scoping Review
- 1Neuroscience Graduate Program, Faculty of Medicine, University of British Columbia, 2215 Wesbrook Mall, Rm 3402, Vancouver, BC V6T 1Z3, Canada
- 2MD Undergraduate Program, Faculty of Medicine, University of British Columbia, 2194 Health Sciences Mall, Rm 317, Vancouver, BC V6T 1Z3, Canada
- 3Djavad Mowafaghian Centre for Brain Health, Department of Medicine (Neurology), University of British Columbia, 2215 Wesbrook Mall, Rm 3439, Vancouver, BC V6T 1Z3, Canada
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons and widespread neural dysfunction. Loss of serotonin (5-HT) signaling and TAR DNA-binding protein 43 (TDP-43) dysfunction have both been identified as contributing factors to disease progression, although their relationship has yet to be fully defined. The objective of this review was to assess whether any mechanistic links exist between serotonergic dysfunction and TDP-43 proteinopathy in ALS. A scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Databases were queried for the peer-reviewed literature concerning ALS pathophysiology, 5-HT, and TDP-43 (1946 to January 2026). Articles were screened and data independently extracted by two reviewers, which were subsequently synthesized qualitatively (n = 14). The current literature suggests that serotonergic dysfunction can be identified early in ALS pathology, indicated by decreased 5-HT concentration, degeneration of raphe projections, and changes in receptor activity. TDP-43 proteinopathy is a defining characteristic of ALS progression, characterized by cytoplasmic mislocalization and aggregation of TDP-43. Additionally, studies have identified bidirectional links between these dysfunctions: TDP-43 impairs serotonergic transmission, and 5-HT deficiency may drive pathological TDP-43 aggregation. Many mechanisms affected by both serotonergic and TDP-43 dysfunction are associated with disease progression including excitotoxicity, metabolic disturbances, and network hyperexcitability. Despite this, there is a lack of direct experimental evidence elucidating connections between these pathologies. Serotonergic dysfunction and TDP-43 proteinopathy may be linked by shared mechanisms in ALS, though specific causality has not been identified. Further research should aim to clarify the connection between these processes and discover therapeutic targets.
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BibTeX
@article{hutchison2026serotonergic,
title = {{Serotonergic Dysfunction and the Interacting Role of TAR DNA-Binding Protein 43 in the Progression of Amyotrophic Lateral Sclerosis: A Scoping Review}},
author = {Lauren L. Hutchison and Makenna M. Parkes and Erik P. Pioro},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16101470},
url = {https://www.mdpi.com/2218-273X/16/10/1470},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Serotonergic Dysfunction and the Interacting Role of TAR DNA-Binding Protein 43 in the Progression of Amyotrophic Lateral Sclerosis: A Scoping Review
AU - Lauren L. Hutchison
AU - Makenna M. Parkes
AU - Erik P. Pioro
PY - 2026
DA - 2026/10/01
JO - Biomolecules
DO - 10.3390/biom16101470
UR - https://www.mdpi.com/2218-273X/16/10/1470
AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons and widespread neural dysfunction. Loss of serotonin (5-HT) signaling and TAR DNA-binding protein 43 (TDP-43) dysfunction have both been identified as contributing factors to disease progression, although their relationship has yet to be fully defined. The objective of this review was to assess whether any mechanistic links exist between serotonergic dysfunction and TDP-43 proteinopathy in ALS. A scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Databases were queried for the peer-reviewed literature concerning ALS pathophysiology, 5-HT, and TDP-43 (1946 to January 2026). Articles were screened and data independently extracted by two reviewers, which were subsequently synthesized qualitatively (n = 14). The current literature suggests that serotonergic dysfunction can be identified early in ALS pathology, indicated by decreased 5-HT concentration, degeneration of raphe projections, and changes in receptor activity. TDP-43 proteinopathy is a defining characteristic of ALS progression, characterized by cytoplasmic mislocalization and aggregation of TDP-43. Additionally, studies have identified bidirectional links between these dysfunctions: TDP-43 impairs serotonergic transmission, and 5-HT deficiency may drive pathological TDP-43 aggregation. Many mechanisms affected by both serotonergic and TDP-43 dysfunction are associated with disease progression including excitotoxicity, metabolic disturbances, and network hyperexcitability. Despite this, there is a lack of direct experimental evidence elucidating connections between these pathologies. Serotonergic dysfunction and TDP-43 proteinopathy may be linked by shared mechanisms in ALS, though specific causality has not been identified. Further research should aim to clarify the connection between these processes and discover therapeutic targets.
SN - 2218-273X
ER -