Abstract Details

Title Spinal Motor Neurons Generated from Induced Pluripotent Stem Cells Derived from Spinal Muscular Atrophy Patients Failed To Cluster Acetylcholine Receptors at the Neuromuscular Junctions

Topic Anterior Horn

Presentation(s) S06 - (-)

Poster/Presentation
Number 007

Objective

Background SMA is a neuromuscular disorder caused by mutations of the survival of motor neuron 1 (SMN1) gene. It remains unclear why the reduction of the ubiquitously expressed SMN protein selectively affects the neuromuscular system in SMA patients. Recent findings suggest that impaired NMJ formation is an important hallmark in SMA. However, the contribution of NMJ pathology to the pathogenesis of SMA remains unclear due to the limited availability of tissue samples.

Design/Methods We established human iPSCs from SMA patients and healthy control subjects. The iPSCs were differentiated into motor neurons, and were co-cultured with mouse myotubes to form NMJ in vitro. The number of motor neurons and the mean area of acetylcholine receptor (AChR) clustering were evaluated by immunocytochemistry.

Results While AChR clustering was successfully established on myotubes co-cultured with control iPSC-derived motor neurons, this was significantly impaired in those cultured with SMA iPSC-derived motor neurons. On the other hand, no significant neuronal death was observed in the SMA iPSC-derived motor neurons compared to those from healthy controls.

Conclusions We successfully developed an in vitro model of NMJ, and by using SMA-iPSCs, we demonstrated that low levels of SMN in the motor neurons are responsible for the impairment of AChR clustering. Our findings imply that the loss of neuromuscular connections appears prior to motor neuronal death, thus suggesting that the NMJ defect is likely to be a major contributing factor to the pathogenesis of SMA. The current in vitro NMJ model is useful to dissect the pathophysiological mechanisms underlying the development of SMA, and to evaluate the efficacy of new therapeutic approaches.

Authors/Disclosures
PRESENTER	No disclosure on file
Blanca R. Vazquez, MD	Dr. Vazquez has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
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