Packard Center scientists have made an important discovery about the normal function of C9orf72 protein, and how mutations may lead to ALS. Discovered five years ago, a sequence of six nucleotides, repeated hundreds or thousands of times in the middle of the C9orf72 gene, is the most common genetic cause of ALS and frontotemporal dementia (FTD). Jiou Wang, a neuroscientist at Johns Hopkins University, and colleagues have found that C9orf72 plays an important role in the cell’s recycling system, a process called autophagy. Their work was published in PLOS Genetics.
“The long-term loss or reduction of C9orf72 protein has the potential to contribute to disease, and needs to be studied further,” Wang said.
Although scientists knew the C9orf72 repeat expansion was harmful, they didn’t know why. The repeat expansion could keep the protein from doing its normal job, which could lead to the disease. Indeed, in patient cells, the level of C90rf72 protein is reduced. In addition, the repeat expansion itself could be toxic. These toxic loss-of-function and gain-of-function options aren’t mutually exclusive and both could be happening simultaneously. In addition, the normal function of the protein still has not been pinned down. Without an understanding of the protein’s normal job in the cell, scientists couldn’t fully understand the role of C9orf72 in ALS and FTD.
In recent months, researchers around the world have reported advances in understanding how the C9orf72 protein functions in the cell, including in autophagy. Work by Wang and colleagues illustrates what happens when the normal function of the C9orf72 protein is lost and provides molecular mechanisms on how the cellular process of autophagy is altered.
excerpt © 2016 Robert Packard Center for ALS Research at Johns Hopkins. All rights reserved.