Neurons, red, created from ALS patients bearing the C9orf72 mutation, show clumps of the RanGAP protein, yellow, in their nuclei, white. The nuclei of other cells are in blue.
Credit: Jeffrey Rothstein laboratory, Johns Hopkins Medicine
The 1st steps in how a common gene mutation causes brain damage associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have been found by Johns Hopkins researchers. Altered C9orf72 gene on human chromosome 9, causes RNA molecules to block critical pathways for protein transport, causing a molecular traffic jam outside brain cell nuclei and affecting their operations and survival. In a proof-of-concept experiment, a molecular therapy eased the jam and restored molecular flow into the cell’s core.
The mutation, the most common of the known genetic risk factors for the diseases, is associated with 40% of inherited ALS cases, 25% of inherited FTD and 10% of noninherited cases of each disease. Both diseases are characterized by degeneration of nerve cells over time. In the case of FTD, the damage causes problems with speech, understanding language and processing emotions. In ALS, the degeneration affects cells in the spinal cord as well as the brain, and patients gradually lose the ability to control their muscles.
C9orf72 mutation, rather than changing one building block of DNA to another, caused a stretch of 6 DNA nucleotides to repeat hundreds of times. Based on the mutated DNA, affected cells create long strands of repetitive RNA. In 2013, Rothstein’s lab identified >400 proteins in the cell with which the repetitive RNA strands might directly interact. “This work identified RanGAP as a critical target of the C9orf72 repeats that could prevent brain cell death when its function was restored.”
In healthy cells, RanGAP helps transport molecules through nuclear pores that connect a cell’s cytoplasm. But in their experiments with both fly and human brain cells made from patients with the ALS-associated C9orf72 mutation, Rothstein and Lloyd discovered RanGAP is clumped up outside the nucleus. Also, proteins that rely on RanGAP for transportation into the nucleus don’t flow through the nuclear pores. Brain tissue from ALS and FTD autopsies also showed similar clumps of RanGAP and other proteins.
In other experiments using fly and human stem cells, they added antisense oligonucleotides which bind to the repetitive RNA strands, blocking them from interacting with the RanGAP protein. The jammed up nuclear pores reopened and proteins moved into the nucleus. Rothstein has launched a collaboration with California-based Isis Pharmaceuticals to pursue the development of a drug that could do the same for patients with ALS and FTD. http://www.hopkinsmedicine.org/news/media/releases/jammed_up_cellular_highways_may_initiate_dementia_and_als
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