Multiple Roles of Transforming Growth Factor Beta in Amyotrophic Lateral Sclerosis

Abstract

Transforming growth factor beta (TGFB) is a pleiotropic cytokine known to be dysregulated in many neurodegenerative disorders and particularly in amyotrophic lateral sclerosis (ALS). This motor neuronal disease is non-cell autonomous, as it affects not only motor neurons but also the surrounding glial cells, and the target skeletal muscle fibers. Here, we analyze the multiple roles of TGFB in these cell types, and how TGFB signaling is altered in ALS tissues. Data reported support a crucial involvement of TGFB in the etiology and progression of ALS, leading us to hypothesize that an imbalance of TGFB signaling, diminished at the pre-symptomatic stage and then increased with time, could be linked to ALS progression. A reduced stimulation of the TGFB pathway at the beginning of disease blocks its neuroprotective effects and promotes glutamate excitotoxicity. At later disease stages, the persistent activation of the TGFB pathway promotes an excessive microglial activation and strengthens muscular dysfunction. The therapeutic potential of TGFB is discussed, in order to foster new approaches to treat ALS.

Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis

“…miR-450a-2-3p and miR-587 have limited information available in the context of the CNS, but both have reported links to the TGF-β/MAPK regulatory pathway (Jahangirimoez et al, 2020;Liu et al, 2020), in line with our pathway analysis. TGF-β is a cytokine with multifaceted effects known to be dysregulated in neurodegenerative disorders, and influences motor neuron survival, susceptibility to glutamate excitoxicity, and non-cell autonomous mechanisms in ALS (Peters et al, 2017;Meroni et al, 2019;Galbiati et al, 2020;Russo and Wharton, 2021). miR-298 is perhaps the most studied of the overlapping DEmiRNAs and is linked to a range of neurologic conditions, including nerve crush injury, spinal bulbar muscular atrophy, and multiple sclerosis (Motti et al, 2017;Pourshafie et al, 2018;Gnanakkumaar et al, 2019).…”

Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling

“…We could recently show that compared to healthy controls, TGFβ and its receptor TGFβ-RII are upregulated in post mortem CNS tissue of ALS patients [14] and that stem cell niche activity is subsequently decreased in the brain and SC. A very recent review highlighted the TGFβ-system to be altered and crucially involved in the disease course in ALS, with dysfunctional signaling in early stages and a persistent over-activation at the clinical stage of disease [30].…”

Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It?

“…Consequently, an increase of IL-1β [ 11 ], IL-6, IL-12p70, TNF-α [ 54 , 79 , 178 , 179 ], IL-17A, macrophage-derived chemokine (MDC), thymus and activation-related chemokine (TARC) [ 86 , 118 ], and migration inhibitory factor (MIF) [ 125 ] were found to be correlated with the more severe behavioral symptoms, while several investigations identified a relationship between the aberrant social communication and IL-6 to be the most relevant to show a correlation with social impairments [ 10 ]. In addition, a positive correlation with social dysfunction was observed with up-regulation of IL-1β [ 7 , 36 ], IL-10, MCP-1 [ 7 , 180 , 181 ], MIP-1β, MIP-1δ, GM-CSF [ 54 , 182 ], and MIF [ 81 , 151 ] and down-regulation of IL-23 [ 83 ], tumor growth factor beta 1 (TGF-β1 [ 183 , 184 ], and TNF-α [ 40 ] in ASD. Stereotypic behavior seemed to correlate with down-regulation of TGF-β1 [ 184 ] and GM-CSF, as well as up-regulation of IL-1β, IL-6, IL-8, IL12p40, TNF-α, and IFN-γ [ 55 , 185 ].…”

“…In addition, a positive correlation with social dysfunction was observed with up-regulation of IL-1β [ 7 , 36 ], IL-10, MCP-1 [ 7 , 180 , 181 ], MIP-1β, MIP-1δ, GM-CSF [ 54 , 182 ], and MIF [ 81 , 151 ] and down-regulation of IL-23 [ 83 ], tumor growth factor beta 1 (TGF-β1 [ 183 , 184 ], and TNF-α [ 40 ] in ASD. Stereotypic behavior seemed to correlate with down-regulation of TGF-β1 [ 184 ] and GM-CSF, as well as up-regulation of IL-1β, IL-6, IL-8, IL12p40, TNF-α, and IFN-γ [ 55 , 185 ]. A restricted pattern of behavior and interests was more pronounced in patients with a high concentration of MCP-1, RANTES, and platelet-derived growth factor subunit B (PDGF-BB) [ 186 ].…”