The X-box binding protein 1 (XBP1) depletion is a contributing factor to the pathogenesis of spinal muscular atrophy (SMA), according to a new study published in Neuropathology and Applied Neurobiology. Therefore, modulating it could be a promising therapeutic approach for patients with the disease.

Three gene therapies for SMA are currently available, but they do not cure the disease and they have limitations in their usefulness. “Novel therapeutic approaches are needed to increase the number of available treatment options for all patients, including original combination therapies,” the authors wrote.

XBP1 plays a role in the unfolded protein response (UPR), which is an adaptive system that restores normal cell function by halting general translation and degrading unfolded proteins. It is activated when unfolded or misfolded proteins accumulate inside cells.

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Previous research has shown that UPR promotes motor neuron death in SMA. Inversely, inhibiting the UPR helps restore cell function when unfolded or misfolded proteins accumulate in the endoplasmic reticulum of cells. They assessed whether it could play a role in the pathology of SMA and whether it could be beneficial for patients.

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The researchers analyzed the expression and activation of key UPR proteins in induced pluripotent stem-cell-derived motor neurons from patients with SMA and an SMA cell line in which survival motor neuron (SMN) expression was rescued. They also used myoblasts and fibroblasts from patients with SMA and SMA mouse models. Finally, they assessed the effect of restoring the IRE1α/XBP1 pathway on the expression of SMN protein and neuroprotection.

The results showed that the IRE1α/XBP1 branch of the UPR was disrupted in SMA and that depletion of XBP1 contributes to the neurodegeneration induced by the disease. When they overexpressed XBP1s in SMA fibroblasts, they found that SMN expression was increased, yet rebalancing the expression of XBP1s in a mouse model of severe SMA led to increased SMN protein expression and motor neuron protection.

The authors recommend that drugs aimed to rebalance the UPR in patients with SMA should be considered as potential candidates for combination therapy.


D’Amico D, Biondi O, Januel C, et al. Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway. Neuropathol Appl Neurobiol. 2022;26:e12816. doi:10.1111/nan.12816