BMP/TGF‐β signaling as a modulator of neurodegeneration in ALS

Abstract

This commentary focuses on the emerging intersection between BMP/TGF‐β signaling roles in nervous system function and the amyotrophic lateral sclerosis (ALS) disease state. Future research is critical to elucidate the molecular underpinnings of this intersection of the cellular processes disrupted in ALS and those influenced by BMP/TGF‐β signaling, including synapse structure, neurotransmission, plasticity, and neuroinflammation. Such knowledge promises to inform us of ideal entry points for the targeted modulation of dysfunctional cellular processes in an effort to abrogate ALS pathologies. It is likely that different interventions are required, either at discrete points in disease progression, or across multiple dysfunctional processes which together lead to motor neuron degeneration and death. We discuss the challenging, but intriguing idea that modulation of the pleiotropic nature of BMP/TGF‐β signaling could be advantageous, as a way to simultaneously treat defects in more than one cell process across different forms of 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).…”

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

“…More generally, interfering with these secreted intercellular signaling pathways in the CNS causes aberrant neurogenesis/gliogenesis, synaptogenesis, and neural circuit remodeling starting in embryonic stages ( Luo et al, 2010 ; Guo et al, 2011 ), and consequently generating defects in sensory processing, coordinated movement, and higher brain function ( Goel et al, 2019 ; Golovin et al, 2021 ). Consistently, autistic and neurodegenerative disorders are characterized by poorly regulated secretion of BMPs, Wnts, and ILPs ( Timberlake et al, 2017 ; de Mello et al, 2019 ; Serafino et al, 2020 ; Russo and Wharton, 2022 ). For instance, an Alzheimer’s disease model accumulates Wnt ligands, causing inflammation of postsynaptic cells ( Ali et al, 2020 ).…”

Neuroprotective effect of Withania somnifera leaves extract nanoemulsion against penconazole-induced neurotoxicity in albino rats via modulating TGF-β1/Smad2 signaling pathway

“…Therefore, aberrant TGF-β signaling pathway, either decrease or increase, could play a crucial role in the pathogenesis of neurodegenerative disorders (Hong et al 2023 ). Previous reports revealed that overexpression of TGF-β1 (the most comprehensively studied TGF-βs) promotes β-amyloid deposition, Tau hyperphosphorylation and NFTs formation in brain tissues accompanied by reactive astrogliosis (Karampetsou et al 2022 ; Lee et al 2010 ; Russo and Wharton 2022 ). The astrocyte-targeted TGF-β1 overexpression drives APP overproduction in astrocytes and promotes Aβ accumulation suggesting an astrocyte-specific mechanism that impaired TGF-β/Smad signaling pathway leading to overactivation of microglia, Aβ deposition, and apoptosis (Diniz et al 2019 ; Ongali et al 2010 ).…”