New publication from Morgan Thomas, PhD

We are excited to share another new study from the lab!

Development of an in vivo, screenable, split-luciferase based model of huntingtin multimerization

Morgan G. Thomas, Simon A. Levy, Meredith H. Jenkins, Morgan Lambert, Bess Frost

Huntington’s disease is a neurodegenerative disorder caused by a poluglutamine (polyQ) expansion in exon 1 of the gene that encodes for the protein huntington (HTT), which drives HTT aggregation. Cellular mechanisms of HTT aggregation are incompletely understood, and existing models are not easily scalable for In vivo screening approaches.

Morgan developed a split-luciferase-based detector system of Htt-Htt interaction in adult Drosophila melanogaster neurons. The system expresses human HTT exon 1 with either a pathogenic 93 glutamine repeat HTT-Q93^LUM or a control 20 glutamine repeat HTT-Q20 ^LUM. When HTT proteins multimerize, the luciferase fragments are brought in close proximity and luminesce, which can be quantified in a standard plate reader. This system, HTT^LUM, enables real-time monitoring of HTT multimerization in living files in a non-leathal nature, which permits subsequent analysis of HTT aggregation, neurotoxicity, and other phenotypes. HTT-induced neurotoxicity was quantified by assessing brain vacuolization, which ws significantly increased in HTT-Q93^LUM Drosophila compared to HTT-Q20^LUM and nontransgenic Drosophila. Proof-of-principal testing with Fosfosal, a salicylic acid derivative, confirmed suppression of HTT Q93 aggregation suggesting that Fosfosal interferes with multimerization. This system serves as a platform for medium-throughput screening followed by mechanistic validation of genetic and pharmacological modifier candidates.

Read the full article here.