Could an overeager response to viral infections predispose certain people to juvenile amyotrophic lateral sclerosis? That is one interpretation of a paper in the March 30 Nature Immunology online.
The authors, at the Icahn School of Medicine at Mount Sinai, New York, report an immune function for senataxin, a gene that is mutated in some cases of early onset ALS. They discovered that the wild-type protein tones down immune responses to viral invaders, keeping inflammation on a tight leash. They theorize that senataxin mutation carriers mount slightly elevated immune responses to infection, which over time could predispose them to neurodegeneration. However, co-senior authors Harm van Bakel and Ivan Marazzi told Alzforum that senataxin might also have additional functions, hence its role in ALS might have nothing to do with viruses.
Senataxin encodes a nucleic acid helicase. It separates the strands of DNA-RNA hybrids that stifle transcription. (Skourti-Stathaki et al., 2011; Yüce et al., 2013). Dominant senataxin mutations cause a form of ALS that usually develops in the teens or 20s (Chen et al., 2004). Recessive, loss-of-function mutations cause a different disease, ataxia with oculomotor apraxia type 2 (AOA2). AOA2 often starts in teenagers as well, causing uncoordinated motion and difficulty with side-to-side eye movements (Moreira et al., 2004).
First author Alexander Rialdi and colleagues were initially interested in transcription factors that control cellular immune functions. Scientists know a fair amount about the cellular program that fends off viruses, such as interferon and the genes it activates. They know less about the mechanisms to turn off inflammation once the threat passes, said Marazzi. Because senataxin was already known to turn off genes that respond to a different stimulus, perturbations to the cell wall in yeast, the authors tested how it acted in mammal cells during viral infection (Kim and Levin, 2011).
Rialdi infected human A549 lung cells with the influenza virus, and profiled genes activated in response. Compared to control cells, those treated with a small interfering RNA against senataxin produced more transcripts of antiviral genes, without making more mRNA overall. They also mounted a stronger defense, retaining fewer viruses than control cells after 24 hours of infection. Rialdi worked with co-first authors Matthew Miller of McMaster University in Hamilton, Canada, and Jessica Ho of the Institute of Molecular and Cell Biology in Singapore. Together, they determined that senataxin was recruited to antiviral genes by the transcription-initiation factor subunit TAF4. Senataxin appears to stop transcription just after the promoter, because Rialdi found that the mRNAs for the antiviral proteins were extremely short in lung cells that express the normal helicase. Cells expressing the mutant version made fewer short transcripts and more full-length mRNAs.
To test the relevance to human disease, the authors repeated their experiments with primary white blood cells and fibroblasts from a person with AOA2 (Suraweera et al., 2007). Compared with those from healthy donors, the AOA2 cells expressed antiviral genes at higher levels in response to infection with the flu virus. To see if similar responses occurred in vivo, the researchers exposed senataxin knockout mice to Sendai virus, a kind of mouse flu. The mice ramped up expression of antiviral genes in their lungs.
These data suggest that a person with a senataxin mutation would likely over-respond to viruses, failing to shut down the body’s response promptly. Over time, successive infections might cause damage, the authors theorized. “We propose that infection has an important role in the initiation or progression of AOA2 and ALS,” they wrote. Bruno Lina of L’Université de Lyon in France wrote that the theory neatly links a genetic predisposition to disease with an environmental trigger. Lina was not involved in the study.
Avindra Nath of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, was cautious about the results, noting that the researchers have not directly associated infection with ALS or AOA2. “The hypothesis they lay down is worth exploring, but it is a stretch at the moment,” said Nath, who was not involved in the study. There was no indication, for example, that senataxin-negative mice infected with virus developed any symptoms of ALS. Scientists have long wondered about a relationship between ALS and infection—particularly because polio virus destroys motor neurons—but never confirmed a connection, Nath said (see Jan 2000 news; Dec 2010 news). He added that senataxin-based ALS, with juvenile onset and slow progression, differs from more typical cases, so the findings might be specific to that form of the disease.
Marazzi and van Bakel agreed that there are alternative explanations for senataxin’s role in ALS. They speculated that senataxin might also regulate non-immune genes, perhaps those involved in response to non-infectious environmental stressors, or genes active specifically in motoneurons. If that were the case, senataxin mutations could precipitate neurodegeneration regardless of viral infection. To investigate further, they are now examining how ALS-linked mutations affect the infection response.—Amber Dance
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