Using patient-derived induced pluripotent stem cells to investigate the role of TrkA signaling in Bipolar Disorder
- Author(s): Miranda, Alannah H
- Advisor(s): Kelsoe, John
- et al.
Bipolar disorder (BD) is a neuropsychiatric disorder that is characterized by afluctuation between depressive and manic phases. In previous studies of a multigenerational family with bipolar disorder, a variant was identified in NTRK1 which codes for TrkA. The variant, rs144901788, causes an amino acid change from glutamate to lysine at position 492. This is located in close proximity to the SHC/Frs2 binding site at tyrosine 490, through which TrkA is known to play a role in cell survival and neurite growth. iPSCs have been generated from lymphoblast cell lines taken from members of the family, both with and without the mutation. These are further differentiated into neural stem cells (NSCs). NSCs derived from the affected patients exhibited differences in gene expression and neurite outgrowth. Downstream signaling of TrkA binding was also evaluated. NTRK1 appeared to be downregulated in the affected neural stem cells. Additionally, NTRK1, as well as it’s ligand nerve growth factor (NGF), have been found to be associated with bipolar disorder in genome wide association studies. Understanding the role of NTRK1 in bipolar disorder may allow for establishing distinct sub-forms of illness that operate through different pathways, yet ultimately culminating in a final disease presentation.