Beyond traditional treatments: vagal nerve stimulation for painful temporomandibular disorders.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of upper and lower motor neurons (MNs), leading to paralysis and death typically within 3–5 years of symptom onset, often due to respiratory failure (Rowland and Shneider, 2001; Hardiman et al., 2011). Approximately 10% of cases are familial ALS, commonly linked to mutations in genes such as , , , and (Valdmanis and Rouleau, 2008; Taylor et al., 2016), while the remaining cases are sporadic ALS, where mislocalization and cytoplasmic aggregation of Transactive Response (TAR) DNA-Binding Protein 43 (TDP-43) are pathological hallmarks observed in 97% of patients (Neumann et al., 2006; Strong, 2010; Ling et al., 2013). TDP-43, an RNA-binding protein, is essential for RNA processing and axonal mRNA transport (Alami et al., 2014). In ALS, its mislocalization from the nucleus to the cytoplasm leads to both loss of function and toxic gain-of-function effects, contributing to neurodegeneration (Taylor et al., 2016, Zhao et al., 2018). These pathological changes are often accompanied by neuroinflammation (NI), driven by activated glial cells and peripheral immune cell infiltration (McCombe et al., 2020; Niccolai et al., 2024b), as well as dysregulated adaptive immune responses involving T helper cells and regulatory T cells (Giovannelli et al., 2020; Jin et al., 2020). Emerging evidence also implicates the gut microbiome (GM) in ALS pathophysiology. Studies in animal models and humans reveal gut dysbiosis, barrier dysfunction, and decreased short-chain fatty acid–producing bacteria, all of which modulate systemic and central immune responses (Figueroa-Romero et al., 2019; Burberry et al., 2020; Niccolai et al., 2021, 2024; Mazzini et al., 2021). Microbiota interventions in ALS models, including butyrate supplementation and fecal microbiota transplantation, have shown potential in attenuating inflammation and disease progression (Zhang et al., 2017; Figueroa-Romero et al., 2019; Burberry et al., 2020). TDP-43 aggregation lies at the intersection of several pathological processes in ALS, including immune dysfunction and microbiome alterations (). This review explores the mechanisms connecting TDP-43 aggregation to neurodegeneration, with a focus on its role in NI, immune dysfunction, and microbiome interactions.