Table 2.
Deregulation of TGF-β signaling pathway associated with various neurological disorders
| Disease | Affected pathway | Mechanism | Impact on pathogenesis | Reference |
|---|---|---|---|---|
| Fragile X syndrome | BMP signaling (U) | Decreased translational inhibition of BMPR2 by FMRP | Increased dendritogenesis and spine number | [37] |
| Williams syndrome | BMP signaling (D?) | Deletion of LIMK1 | Abnormal synapse morphology and function | [51] |
| Angelman syndrome | BMP signaling (U) | Decreased BMPR1A degradation by UBE3A | Abnormal spine formation | [52] |
| Mowat-Wilson syndrome | BMP signaling (U or D) | Deregulation of SIP1 | Defective neural crest formation | [53,54] |
| Troyer syndrome | BMP signaling (U) | Decreased endocytotic degradation of BMPR2 by SPARTIN | Increased synapse formation and neurodegeneration | [55,56] |
| SPG3A | BMP signaling (U) | Decreased endocytotic degradation of BMPR2 by ATL1 | Abnormal microtubule dynamics and axon guidance? | [57–59] |
| SPG4 | BMP signaling (U) | Decreased endocytotic degradation of BMPR2 by SPAST | Abnormal microtubule dynamics and axon guidance? | [57,60] |
| SPG6 | BMP signaling (U) | Decreased endocytotic degradation of BMPR2 by NIPA1 | Abnormal synapse formation, microtubule dynamics, and axon guidance | [16,57,60,61] |
| Alzheimer’s disease | TGF-β signaling (U or D) | Deregulation of TGF-β1, Smad7, nuclear R-Smad/Co-Smad. | Aβ accumulation, aberrant microglia activation, and increased neurodegeneration | [62–71] |
| BMP signaling (U) | Elevation of BMP4 and BMP6 | Inhibition of neurogenesis | [72–75] | |
| Parkinson’s disease | TGF-β signaling (U or D) | Deregulation of ligands and receptors | Degeneration of DA neuron | [76–79] |
| BMP signaling (D) | Deregulation of ligands and receptors | Inhibition of DA neuron differentiation and protection from neurodegeneration | [80–87] | |
| Huntington’s disease | TGF-β signaling (U or D) | Deregulation of neuronal and circulating TGF-β1 | Increased neurodegeneration? | [88–92] |
| BMP signaling (U) | N.D. | Increased dendritic branching and synapse size | [93] | |
| Amyotrophic lateral sclerosis | TGF-β signaling (U or D) | Deregulation of ligands and Smad2/3 protein stability | Inhibition of neuroprotection and increased axon degeneration | [94–98] |
| BMP signaling (U or D) | Deregulation of receptor trafficking | Impaired synapse growth | [99–102] | |
| Multiple sclerosis | TGF-β signaling (U) | N.D. | Inflammation? | [103–105] |
| BMP signaling (U) | Deregulation of BMP2, BMP4, BMP5 and noggin | Inhibition of neuronal differentiation and myelination | [106–112] |
U, D, and N.D. stand for ‘Up’, ‘Down’ and ‘not determined’, respectively.