ALS Research Update: Spring 2015

by Margaret Wahl on Wed, 2015-04-01 13:34

Several research groups have published new findings about how various gene flaws cause ALS and how their effects might be counteracted

Article Highlights:
  • MDA-supported Adrian Israelson and colleagues have found that a protein called MIF can counteract the damaging effects of ALS-causing mutations in the SOD1 gene.
  • Axel Freischmidt at Ulm University in Germany and colleagues have found that mutations in a gene called TBK1 can lead to ALS, apparently through reducing the effectiveness of a cellular garbage disposal system.
  • Mutations in the senataxin gene, identified as a cause of juvenile-onset ALS by MDA-supported researchers in 2004; now, new findings show the pathway to disease may be caused by a faulty response to viral infections.
  • A section of expanded DNA in the C9ORF72 gene was recently discovered to be a genetic cause of ALS; now, new findings show that modifying the DNA through "hypermethylation" can dial back the damaging effects of this mutation.

Understanding the many roads that can lead to amyotrophic lateral sclerosis (ALS) is a painstaking but necessary prerequisite to development of disease-modifying treatments. Recently, several research teams have made contributions to this effort. A 2011 MDA career development grant to Adrian Israelson, who was then at the University of California, San Diego, was crucial to the finding that the MIF protein counteracts the effects of ALS-causing mutations in the SOD1 gene.

Getting SOD1 back into shape

It's been known since the early 1990s that mutations in the gene for the SOD1 protein can cause human ALS, as well as an ALS-like disorder in mice. Mutations in the SOD1 gene cause the SOD1 protein to fold into abnormal shapes, making it toxic to nerve cells. Now, scientists funded in part by MDA have shown that a protein called MIF can act as a "chaperone" for the SOD1 protein, counteracting the misfolding of this protein and thereby reducing the damage it does to cells. MDA research grantee Adrian Israelson at Ben-Gurion University of the Negev in Beer Sheva, Israel, and colleagues, published their findings online March 19, 2015, in the journal Neuron. "Identification of MIF as an intracellular chaperone that stimulates folding/refolding of misfolded SOD1 suggests a new avenue for therapy develpment in ALS," the authors say, noting that some of MIF's other, potentially harmful activities would need to be blocked before MIF could be considered as a possible treatment for SOD1-related ALS.

New ALS gene ID points to faulty garbage disposal system

The gene for a protein called TBK1 can, when flawed, lead to ALS, adding to the approximately 30 genes that have so far been linked to this disease. The ALS-causing flaws (mutations) identified by Axel Freischmidt at Ulm University in Germany, and colleagues, appear to reduce the function of TBK1, a protein that normally helps break down defective cellular proteins in a cellular cleanup and garbage disposal pathway known as "autophagy."

TBK1 mutations can cause ALS even when present in only one of the two TBK1 genes present in every cell, which is unusual for loss-of-function mutations. Usually, one functional gene of a set of paired genes is sufficient to protect against development of a disease.

The authors say the findings, published online March 24, 2015, in Nature Neuroscience, emphasize the importance of TBK1 and possibly of autophagy in maintaining the health of nerve cells over a lifetime.

Understanding senataxin shows how viruses may trigger ALS

Back in 2004, an international research group supported in part by MDA found that flaws in the gene for the senataxin protein could cause a juvenile-onset, slowly progressive form of ALS known as ALS4. However, the normal functions of the senataxin protein were barely understood. Now, Matthew Miller at McMaster University in Hamilton, Ontario, Canada, and colleagues, have found that the senataxin protein normally plays a role in controlling the body's response to viral infection, helping to ensure that the response is appropriate and not so extreme that it could be harmful. Abnormalities in senataxin could, the evidence suggests, result in an excessive response to a viral infection and, over time, progressive deterioration of tissues. The findings, published online March 30, 2015 in Nature Immunology, suggest a possible link between viral infections and senataxin-linked ALS and support the idea that infection has an important role in the intiation or progression of ALS4.

Dialing back C9ORF72 activity

The addition of more than the usual number of "methyl" groups (each methyl group is one carbon atom and three hydrogen atoms) to a common ALS-causing DNA mutation in a gene called C9ORF72 appears to tone down the effets of this mutation, offering some protection for nerve cells carrying this genetic flaw.

Understanding how this process, which is called "hypermethylation," operates in this setting, may lead to new insights about how an abnormal expansion of DNA in the C9 gene harms nerve cells and causes disease. Perhaps more important, the phenomenon presents scientists with potential leads for therapy development to treat C9-related ALS.

DNA methylation (the addition of methyl groups to DNA) is one type of "epigenetic" modification. Epigenetic modifications (changes that are "on top of" genes) are alterations that can be made to DNA or related structures that affect the way a gene is processed by a cell without changing the sequence of the DNA itself. In this case, it appears that excessive methylation (hypermethylation) reduces the activity of the C9ORF72 gene – a benefit when this gene is mutated.

Corey McMillan at the University of Pennsylvania, and colleagues, who published their findings online March 20, 2015, in Neurology, say they "suggest that therapeutic agents that aim to increase C9ORF72 methylation or decrease C9ORF72 transcription [gene activity] may have neuroprotective benefits in individuals with a C9ORF72 expansion.






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