Honolulu: Potential New Gene on the ALS List

Series - American Society for Human Genetics Annual Meeting:

Researchers at the University of Michigan reported today on a new gene they suspect of contributing to amyotrophic lateral sclerosis (ALS) in a poster presentation at the American Society of Human Genetics annual meeting in Honolulu, Hawaii. First author Shirley Rainier, principal investigator John Fink, and colleagues found mutations in neuropathy target esterase (NTE) in three people out of 100 with ALS, while no such mutations were found in control subjects. NTE mutations have already been linked to another motor neuron disorder, and the protein’s activity is also damaged in neurodegeneration caused by organophosphates.

Residing in the endoplasmic reticulum, NTE is an enzyme that breaks down phosphatidyl choline, a major component of membranes. The Drosophila homolog, Swiss Cheese, has also been shown to regulate cyclic AMP-dependent protein kinase (Bettencourt da Cruz et al., 2008). The enzyme has been linked to organophosphate-induced delayed neuropathy; the organophosphates found in some pesticides have been proposed to cause neurodegeneration by inhibiting NTE (reviewed in Chang and Wu, 2009).

Rainier and Fink previously found NTE mutations in two families with a motor neuron disease similar to, but distinct from, classical ALS (Rainier et al., 2008). Patients displayed slowly progressive symptoms with right-to-left symmetry of motor impairment, Fink said, unlike the rapidly progressing and generally asymmetrically presenting ALS.

Following that study, the authors wondered if NTE mutations might be more widespread. Accordingly, they sequenced the gene’s esterase domain in 100 people with ALS, and an additional 105 control participants. Among the ALS subjects, three were heterozygous for point mutations in the enzyme. The 3 percent rate is small, but statistically significant, Fink said. “In the world of ALS, this is a fairly high number,” he added, noting that the most common known mutation, in superoxide dismutase 1, accounts for fewer than 10 percent of ALS cases. “This gives us new insights into the biochemistry, and maybe treatment, of ALS.”

In an e-mail to ARF, Jeffrey Rothstein of Johns Hopkins University in Baltimore, Maryland, who was not involved in the research, called the findings “interesting, but in need of much more work to see if it is really relevant to sporadic ALS.” Cell biology evidence, showing that the mutations actually change NTE activity in a manner injurious to the cell, is necessary, Rothstein wrote.

A recent paper from the laboratory of Paul Glynn at the University of Leicester, UK, supports the idea of NTE involvement in neural health. He and colleagues found that mice lacking NTE expression experienced progressive degeneration of spinal neuron axons combined with mild but progressive hindlimb motor problems (Read et al., 2009). Glynn noted that mice heterozygous for NTE mutations are fine, but speculated that humans might require more than 50 percent of the enzyme’s normal activity. “If the heterozygous mutations found in the three ALS patients caused a major loss of NTE activity…this might be sufficient to ultimately cause axonal degeneration,” he wrote in an e-mail to ARF.

The research does not necessarily indicate that NTE mutations directly cause ALS, Fink noted; it is also possible that diminished NTE function raises one’s risk and could lead to disease when combined with other genetic or environmental factors.—Amber Dance.

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References

Paper Citations

  1. Bettencourt da Cruz A, Wentzell J, Kretzschmar D. Swiss Cheese, a protein involved in progressive neurodegeneration, acts as a noncanonical regulatory subunit for PKA-C3. J Neurosci. 2008 Oct 22;28(43):10885-92. PubMed.
  2. Chang PA, Wu YJ. Motor neuron diseases and neurotoxic substances: a possible link?. Chem Biol Interact. 2009 Jul 15;180(2):127-30. PubMed.
  3. Rainier S, Bui M, Mark E, Thomas D, Tokarz D, Ming L, Delaney C, Richardson RJ, Albers JW, Matsunami N, Stevens J, Coon H, Leppert M, Fink JK. Neuropathy target esterase gene mutations cause motor neuron disease. Am J Hum Genet. 2008 Mar;82(3):780-5. PubMed.
  4. Read DJ, Li Y, Chao MV, Cavanagh JB, Glynn P. Neuropathy target esterase is required for adult vertebrate axon maintenance. J Neurosci. 2009 Sep 16;29(37):11594-600. PubMed.

Further Reading

Papers

  1. Winrow CJ, Hemming ML, Allen DM, Quistad GB, Casida JE, Barlow C. Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity. Nat Genet. 2003 Apr;33(4):477-85. PubMed.

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