Research News

Preclinical research from Cleveland Clinic discovered a genetic cause and potential intervention for microcephaly, a neurodevelopmental disorder that causes an infant's head to be smaller than others of the same age and sex.

Investigators led by senior author Michelle Longworth, PhD, associate staff in Inflammation & Immunity, identified the genetic shifts that lead to microcephaly in preclinical models. This groundbreaking work offers direction for future human study and therapeutic development to prevent microcephaly, which has treatment options, but no cure.

Published in Nature Communications, the study identifies a connection between normal brain development and condensins, protein complexes involved in genome organization. Dr. Longworth's lab previously discovered that condensins suppress DNA segments called retrotransposable elements (RTE), that can move around to cause mutations. Previous research also found mutated condensins in microcephaly patients.

Dr. Longworth's team knocked down the condensins to see whether condensin mutations, and therefore uncontrolled RTE, could explain microcephaly head development. Preclinical models showed that knocking down condensins led to neural stem cell death and ultimately caused microcephaly. The researchers also observed strongly pronounced gender bias, where male preclinical models exhibited a pronounced tendency toward more severe microcephaly.

"This finding is based on more than 10 years of our lab's research into RTE, key in the brain development's underlying mechanisms" says Dr. Longworth. "Our study has shown that when we deplete condensins and other RTE repressors in the fruit fly brain, this triggers cell death not just in progenitor cells, but in neighboring cells, which is also a new finding we will continue to investigate."

The team also discovered using nucleoside reverse transcriptase inhibitors, NRTI's – FDA-approved therapies for HIV - can prevent microcephaly in preclinical models. The therapies inhibit processes necessary to RTE replication.

"This has been an extremely collaborative study," Dr. Longworth says. "Many members of my team, including postdocs, lab technicians and undergraduate students, contributed to making these first-of-their-kind discoveries. We've laid the foundation for future exploration of causative roles of RTEs in other microcephaly models."

The Longworth team is now investigating these discoveries in human neural stem cells and delving deeper into understanding how these mobile elements cause stem cell death – a critical step toward developing innovative therapeutic interventions toward preventing or mitigating microcephaly.

This research was supported by the Lisa Dean Moseley Foundation and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.