Disrupted Transforming Growth Factor-β Signaling in Spinal and Bulbar Muscular Atrophy

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins accumulate in neurons and thereby induce transcriptional dysregulation, the downstream molecular events have remained elusive. Here, we examined whether TGF-␤ signaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3, a key step in TGF-␤ signaling, is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human AR. A similar finding was also observed in the motor neurons, but not in Purkinje cells, of SBMA patients. The pathogenic AR, the causative protein of SBMA, inhibits the transcription of TGF-␤ receptor type II (T␤RII) via abnormal interactions with NF-Y and p300/CBP-associated factor. Furthermore, overexpression of T␤RII dampens polyglutamine-induced cytotoxicity in a neuroblastoma cell line expressing the pathogenic AR. The present study thus indicates that disruption of TGF-␤ due to the transcriptional dysregulation of T␤RII is associated with polyglutamine-induced motor neuron damage in SBMA.

Relay of retrograde synaptogenic signals through axonal transport of BMP receptors

“…The authors propose that increasing BMP signaling could be a possible therapeutic approach for SMA patients. Our results describing the mechanism of BMP signaling in Drosophila motoneurons helps understand the pathological consequences of pathway disruption and will open new avenues to understand human neurodegenerative disorders that involve TGFb signaling (Bayat et al, 2011;Katsuno et al, 2010). Additionally, our results in conjunction with other reports (Bökel et al, 2006;Di Guglielmo et al, 2003) suggest that signaling endosome traffic is a general mechanism in TGF-b signaling.…”

NF‐Y‐dependent regulation of glutamate receptor 4 expression and cell survival in cells of the oligodendrocyte lineage

“…This conclusion is complemented by studies indicating NF‐Y deregulation as a contributor to neurodegenerative processes in several polyglutamine (polyQ) expansion diseases (Huang, Ling, Yang, Li, & Li, 2011; Katsuno et al, 2010; Yamanaka et al, 2008). In each case, disrupted NF‐Y activity is associated with the accumulation of mutated polyQ‐bearing proteins.…”

“…This is exemplified in spinal and bulbar muscular atrophy, a polyQ disorder involving the accumulation of mutated androgen receptor (AR) protein in brain stem and spinal cord motorneurons. In this condition transcription of transforming growth factor‐ß receptor type‐II (TGFßR‐II), a pro‐survival NF‐Y target, is impaired due to abnormal associations between NF‐Y and mutated AR that probably prevent NF‐Y from binding and activating TGFßR‐II (Katsuno et al, 2010). Similarly, mutant Huntington, the pathological protein underlying Huntington's Disease (HD), forms inappropriate interactions with NF‐Y leading to reduced transcription of heat shock protein 70 (HSP70), an NF‐Y target expected to aid in the clearance of mutated proteins.…”

Activation of Transforming Growth Factor-β/Smad Signaling Reduces Aggregate Formation of Mislocalized TAR DNA-Binding Protein-43

“…TGFβ was shown to be neuroprotective in ischemic brain damage [22] and axonal injury [23]. Recently, disrupted TGFβ/Smad signaling was reported to be associated with the motor neuron damage seen in a human late-onset lower motor neuron disease [24]. Moreover, TGFβ stimulation was shown to activate autophagy in epithelial cells [25], human hepatocellular carcinoma cell lines [26], and mesangial cells [27].…”