What Autism can Teach us about Brain Cancer
Glioblastoma multiforme, or GBM, is a deadly cancer with median survival of only 12-15 months. Recently, we found a gene that had been previously implicated in autism to also contribute to GBM. The gene NHE9 makes a protein that exchanges sodium ions for hydrogen ions (also called protons) across the boundaries of endosomes, hence it’s moniker “sodium-hydrogen exchanger”. But what are endosomes and why is the function of NHE9 important?
Highway Traffic: All cells contain many “cargo packages” surrounded by membranes, depicted in the expanded view as a blue compartment in the figure below. These so-called endosomes carry newly minted proteins to specific destinations throughout the cell and haul away old proteins for destruction. Key to their “shipping speed” is the level of acidity inside the endosomes. Acidity relates to the number of protons, which are controlled by balancing the activity of “pumps” that push protons into endosomes to increase their acidity with that of “leaks,” like the protein NHE9, that remove protons.
There’s a Hole in the Bucket: You can think of endosomes as leaky buckets of water. Altering either the faucet or the leak rate can dramatically change the water level in the bucket. In autism, NHE9 is mutated and non-functional. In the absence of proton leak, the endosomes become too acidic and prematurely clear away important proteins on nerve ends, leading to neurological dysfunction. Helper cells called astrocytes cannot clear away neurotransmitter signals fast enough, and this leads to hyperexcitability or seizures associated with autism.
Too Much of a Good Thing: in contrast to autism, NHE9 is overactive in brain cancer, causing endosomes to leak too many protons and become too alkaline. This slows down the “shipping rate” of cancer-promoting cargo and leaves them on the cell surface for too long where they inappropriately prolong signals of growth and migration, the two main characteristics of invasive cancer cells. Fortunately, when the leak is plugged by inhibiting NHE9 with drugs, tumor growth is blocked. Currently, the drugs are not good enough to use on patients, so an important step going forward will be to discover better drugs that target NHE9. These could be used in combination with other drugs for treatment of this deadly disease.
Paper: A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma. Kondapalli et al. (2015) Nature Communications http://goo.gl/dAa5NG
Johns Hopkins News Story: http://goo.gl/XAsGDb
A Part of the Puzzle: NHE9 and Autism https://plus.google.com/u/0/+RajiniRao/posts/fsNzo1yKsQG