Work

Serotonergic Dysfunction and the Interacting Role of TAR DNA-Binding Protein 43 in the Progression of Amyotrophic Lateral Sclerosis: A Scoping Review

Year: 2026

Type: review

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of mo-tor 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 rela-tionship 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 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). 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 serotonin deficiency may drive patholog-ical 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.

Source: Biomolecules

DOI: 10.3390/biom16101470

Authors: Lauren L. Hutchison, Makenna M. Parkes, Erik P. Pioro

Language: English

Topic: Amyotrophic Lateral Sclerosis Research

Subfield: Clinical Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,258

Funder: Faculty of Medicine, University of British Columbia