Development of a disease model for narcolepsy


March 5, 2014 - 1:00pm
NW 243
About the Speaker
Florian Merkle (Eggan Lab)

Narcolepsy is a debilitating and incurable sleep disorder caused by the specific loss of a small group of hypothalamic neurons that secrete the neuropeptide hypocretin (HCRT). The cause of HCRT neuron loss in narcolepsy is unknown, but recent evidence implicates the DNA methyltransferase DNMT1 in both sporadic and familial forms of the disease. To probe the mechanistic contribution of DNMT1 to HCRT neuron loss, I developed a method to differentiate human pluripotent stem cells into HCRT neurons and generated a knock-in HCRT-GFP reporter cell line. To model autosomal dominant familial narcolepsy, I used the Cas9/CRISPR system to introduce the disease-causing mutation into the HCRT-GFP reporter line. To complement this familial work, I also generated induced pluripotent stem cells from patients with sporadic narcolepsy in order to generate HCRT neurons harboring genetic variants the might contribute to sporadic narcolepsy. I will discuss my plans to utilize these resources to shed light on the molecular basis of HCRT neuron loss in particular, and neurodegeneration in general.