Double duty: Early research reveals how a single drug delivers twice the impact in fragile X
Like many neurological diseases, there’s a lot we don’t understand about fragile X syndrome. But, after studying the disorder for several years, Lynne Maquat’s lab knew two important things: the enzyme AKT, which plays a key role in cell growth and survival, and the quality control pathway known as NMD (nonsense-mediated mRNA decay), are both in overdrive in fragile X.
In a new study in the journal Molecular Cell, the team reveals how these two major players interact, highlighting a complex molecular dance that could inform the development of future treatments for fragile X syndrome.
Two paths to pursue
AKT is a hub for cell signaling, helping cells communicate about important processes like cell growth, proliferation and protein production. When cells are stressed — for example, in cancer, diabetes, heart disease and neurological disorders, including fragile X — AKT can send too many (or too few) signals or messages as part of a cell survival mechanism.
NMD is like a molecular guide that helps our cells make smart decisions that (in most cases) improve cellular function and contribute to good health. For example, NMD supports gene expression by flagging and destroying mRNAs (messenger RNAs) that are carrying faulty genetic instructions that could lead to disease. It also helps our cells adjust to changes in development and in their environment, and more rapidly respond to certain stimuli.
Co-lead study authors Hana Cho, Ph.D., and Elizabeth Abshire, Ph.D., discovered how AKT and NMD interact in the context of fragile X:
- The team started with neural stem cells that lack the FMRP protein, which is needed for normal brain development. Fragile X syndrome occurs when individuals don’t make this protein.
- They showed that when AKT is in overdrive (as it is in fragile X), it turns on a molecule that is necessary for NMD to occur.
- Consequently, when AKT is high, NMD is hyperactivated.
Drug double whammy
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