Abstract
Amyotrophic lateral sclerosis (ALS) represents a fatal orphan disease with high unmet medical need, and a life time risk of approx. 1/400 persons per population. Based on increasing knowledge on pathophysiology including genetic and molecular changes, epigenetics, and immune dysfunction, inflammatory as well as fibrotic processes may contribute to the heterogeneity and dynamics of ALS. Animal and human studies indicate dysregulations of the TGF-β system as a common feature of neurodegenerative disorders in general and ALS in particular. The TGF-β system is involved in different essential developmental and physiological processes and regulates immunity and fibrosis, both affecting neurogenesis and neurodegeneration. Therefore, it has emerged as a potential therapeutic target for ALS: a persistent altered TGF-β system might promote disease progression by inducing an imbalance of neurogenesis and neurodegeneration. The current study assessed the activation state of the TGF-β system within the periphery/in life disease stage (serum samples) and a late stage of disease (central nervous system tissue samples), and a potential influence upon neuronal stem cell (NSC) activity, immune activation, and fibrosis. An upregulated TGF-β system was suggested with significantly increased TGF-β1 protein serum levels, enhanced TGF-β2 mRNA and protein levels, and a strong trend toward an increased TGF-β1 protein expression within the spinal cord (SC). Stem cell activity appeared diminished, reflected by reduced mRNA expression of NSC markers Musashi-1 and Nestin within SC—paralleled by enhanced protein contents of Musashi-1. Doublecortin mRNA and protein expression was reduced, suggesting an arrested neurogenesis at late stage ALS. Chemokine/cytokine analyses suggest a shift from a neuroprotective toward a more neurotoxic immune response: anti-inflammatory chemokines/cytokines were unchanged or reduced, expression of proinflammatory chemokines/cytokines were enhanced in ALS sera and SC postmortem tissue. Finally, we observed upregulated mRNA and protein expression for fibronectin in motor cortex of ALS patients which might suggest increased fibrotic changes. These data suggest that there is an upregulated TGF-β system in specific tissues in ALS that might lead to a “neurotoxic” immune response, promoting disease progression and neurodegeneration. The TGF-β system therefore may represent a promising target in treatment of ALS patients.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a progressive loss of upper and lower motor neurons [1]
In order to investigate whether circulating TGF-β ligand levels differ between controls and ALS patients, serum levels of TGFβ1 and TGF-β2 were determined via electrochemiluminescence
ALS patients exhibited significantly enhanced circulating levels of the general proinflammatory markers SAA (p = 0.0006; Figure 3C) and CRP (p = 0.022; Figure 3D) as well as angiogenic factors VEGF (p < 0.0001; Figure 3E), VEGF-C (p = 0.027; Figure 3F), Tie-2 (p < 0.001; Figure 3G), and a strong trend toward increased levels of PIGF (p = 0.059; Figure 3H). These results demonstrate a more pronounced proinflammatory immune response in ALS patients compared to controls
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a progressive loss of upper and lower motor neurons [1]. The broad clinical phenotype in combination with few disease biomarkers results in late diagnosis with advanced disease progression [2, 3]. In this context, the TGF-β system has emerged as a potential target due to its involvement in essential cellular and physiological processes, such as proliferation, cell differentiation, and growth; further, TGF-β is involved in immune regulation, stem cell activity and fibrosis. Human skeletal muscle biopsies and skeletal muscle samples from mSOD1 mice revealed enhanced TGF-β1 mRNA and protein expression with increased signaling, fibrosis, and disease progression [8, 9]. In contrast to the acute anti-inflammatory properties of TGF-β, a persistent elevated system activity might promote ALS progression by interacting with three different systems, namely (i) the immune response, (ii) the activity of the adult neurogenic niche, and (iii) fibrotic scarring
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
