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Oct 25
2016

Molecular mechanisms of ALS converge in new study

Packard Center News
In a new study in Cell, Packard scientist J. Paul Taylor, shows that the abnormal toxic proteins produced by the repeat expansion in

In the five years since the discovery of the repeat expansion in the C9orf72 gene, the most common genetic cause of ALS and frontotemporal dementia (FTD), scientists have made tremendous insights into how this alteration leads to disease. Because this repeat expansion is the cause of disease in as many as 40 percent of those with familial ALS and 5 to 10 percent of those with sporadic disease, understanding how C9orf72 could provide valuable information about the cause of illness.

In a new study in Cell published on October 20, Packard scientist J. Paul Taylor, an HHMI Investiagtor and biologist at St. Jude Memorial Children’s Hospital in Memphis, Tennessee, shows that the abnormal toxic proteins produced by the repeat expansion interfere with the formation of membrane-less organelles, such as the nucleolus, the nuclear pore complex, and stress granules. These toxic proteins also interact with proteins with low complexity domains, altering their liquid assembly and changing their properties.

The results of this study, Taylor says, reveal a convergence in the mechanism underlying seemingly distinct genetic forms of ALS, creating a more comprehensive picture of the molecular underpinnings of ALS.

The C9orf72 repeat expansion consists of a series of six nucleotides that is repeated hundreds or thousands of times. One of the ways that this repeat causes ALS is by gumming up the cellular machinery that turns DNA into protein. The machinery “reads” the repeat both forwards and backwards, creating small proteins called dipeptide repeats (DPRs) that are made up of a sequence of two amino acids. Previous work has shown that some of these DPRs, especially those containing the amino acid arginine, are exquisitely toxic to cells.

Taylor and colleagues began by investigating the DPR interactome, the full range of proteins with which the DPRs bind. Their work revealed that the two arginine-containing DPRs, known as polyGly-Arg (GR) and polyPro-Arg (PR), interacted with low complexity domains found in many RNA-binding proteins. Interestingly, several of these same RNA-binding proteins have been linked to ALS, including TDP43, hnRNPA1, and FUS. Low complexity domains in proteins, so-named because they represent regions with a very limited variety of amino acids, were recently discovered to be responsible for the assembly of membrane-less organelles.

Both GR and PR were localized to very specific areas of the nucleolus, specifically the liquid-like granular component, where the earliest stages of ribosome assembly take place. The presence of GR and PR in the granular component interferes with the normal biophysical properties of this region, creating problems with the cell’s ability to build ribosomes. Fluorescently tagging these DPRs showed that they obstruct normal nucleolar dynamics and function by binding to proteins with low complexity domains. They also interfere with the dynamics and function of other membrane-less organelles, including stress granules, dense assemblies of protein and RNA that appear to protect the cell during stress.

Taken together, these results help to unite several different fields of inquiry into how the C9orf72 repeat expansion and mutations in several different RNA-binding proteins all cause the same disease, ALS. In particular, the arginine-containing DPRs affect the biophysical properties unique to proteins with low-complexity domains, which play an important role in the formation and function of membrane-less organelles. This helps to create a broad, comprehensive picture of ALS pathogenesis that is important for understanding the molecular causes of disease, Taylor says. 

 

 

Photo Credit:  Howard Hughes Medical Institute

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