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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the motor system
The analysis of muscle lysates from ALS patients indicated a strong increase of TGFB1 protein [90]. In these samples, TGFB1 immunoreactivity has been detected in macrophages and lymphocytes surrounding the fibers and suggesting inflammatory infiltrated cells as the TGFB1 source, we reported that the expression of mutant SOD1 (mutSOD1) in C2C12 cells stimulates Tgfb1 expression [28], and C2C12 cells are able to respond to transforming growth factor beta (TGFB), increasing small mother against decapentaplegic (SMAD) production and phosphorylation [90]
The imbalance of TGFB signaling has been linked to ALS progression
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting the motor system. It implicates different cell types: motor neurons are the main affected cells, but glial and skeletal muscle cells are strongly implicated and able to deeply modulate the disease onset and course. We will briefly describe why ALS is considered a non-cell-autonomous disease, and the general features of the TGFB family; we will analyze the roles of TGFB on the multiple cell types involved in ALS, and we will discuss the TGFB pathway as a potential pharmacological target. We will only briefly mention the multiple effects of TGFB on the immune system in ALS, as it is a field that deserves a separate discussion, due to the various and multifaceted roles exerted by TGFB on this system
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