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ALS Alert Newsletter

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Dec 20
2016

New research helps to identify function of important ALS protein

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.

Packard 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.

Wang and colleagues created mouse models lacking C9orf72 protein to understand the function of the protein: one set was heterozygous and had one normal copy of the mouse C9orf72 and the other copy edited out; and the other set had both copies of the mouse C9orf72 gene edited out. The mice that lacked both copies of C9orf72 had significantly increased mortality: 50% had died after 600 days, compared to 20% in the heterozygotes. There was not obvious neuronal death, however functional defects of the nervous system were possible. Cellular and molecular studies revealed defects in the mTOR signaling pathway, a central pathway that senses stresses related to nutrient, oxygen, and energy levels and helps to maintain metabolic balance.

The reduction in mTOR activity leads to an increase in the production of TFEB, a protein that acts as the master on/off switch for genes that control autophagy and the synthesis of lysosomes, which help to digest cellular debris. TFEB helps to balance the activity of the mTOR pathway with the cell’s recycling capacity. A further set of experiments from the C9orf72 knockout mice showed that their brains showed profoundly increased activity of TFEB and the downstream proteins that instructed the cell to produce autophagy machineries.

Intriguingly, unlike recent reports that autophagy is inhibited when C9orf72 protein is lost, Wang and colleagues observed an increase in autophagy activities, especially under nutrient starvation stress. This finding, however, is consistent with the observed decrease in mTOR activity and the enhanced TFEB activity in the absence of C9orf72. These experiments suggest that C9orf72 plays an important role in keeping the optimal balance in the nutrient sensing and autophagy pathways.

Taken together, this study shows that the C9orf72 protein helps to regulate the important metabolic pathways in the cell, and that reduction of C9orf72 functions disrupts the balances important for health. Although it’s still not clear precisely what role the newly recognized functions of C90rf72 plays in ALS and FTD, Wang says that increasing evidence suggests loss of C9orf72 contributes to disease.

“An increasing number of ALS genes points to involvement of autophagy. Uncovering the functions of C9orf72 protein will help us better understand the core process of this devastating disease,” Wang said.

-Carrie Arnold