Poster abstracts
Poster number 108 submitted by Amelia Pfaff
Modeling TARDBP-Associated ALS Using iPSC-Derived Neuromuscular Junctions for Mechanistic and Therapeutic Discovery
Amelia A. Pfaff (Pharmacology, CWRU), Helen C. Miranda (Genetics and Genome Sciences, CWRU)
Abstract:
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects brain and spinal cord neurons, leading to a gradual loss of muscle control and function. One of the pathophysiological hypotheses for the disease is that ALS is preceded by dysfunction or degeneration of neuromuscular junctions (NMJs), which are highly specialized synaptic connections between motor neurons and skeletal muscle. Although less than 10% of ALS cases are caused by familial genetic mutations, pathological mislocalization and aggregation of the RNA-binding protein TDP-43 (encoded by the TARDBP gene) is found in 95% of all ALS cases. Two recurrent glycine-rich-region mutations, M337V and Q331K, accelerate TDP-43 aggregation, leading to the disease state. Current animal models, particularly mouse models, do not fully recapitulate the architecture and physiology of human NMJs, limiting their utility for mechanistic studies and drug discovery. To overcome this limitation, our laboratory has developed a human induced pluripotent stem cell (iPSC)-derived NMJ model in which motor neurons and skeletal myotubes self-assemble into functional neuromuscular junctions. This two-dimensional co-culture system allows for direct interrogation of motor neuron–muscle interactions, quantification of NMJ structure and function, and medium-throughput screening of candidate therapeutics.
Keywords: TDP43, iPSC