ALS Research Briefs: Protein Biomarker and Stem Cells

Protein test predicts ALS progression

It’s known that levels of a protein called phosphorylated neurofilament heavy subunit (PNF-H) are increased in the spinal fluid of people with amyotrophic lateral sclerosis (ALS). Now, a team of researchers has demonstrated that higher levels of PNF-H in both the blood and spinal fluid are associated with a faster rate of ALS disease progression and shorter survival time.

PNF-H proteins are released when motor neurons — the muscle-controlling nerve cells that are lost in ALS — are damaged.

In an earlier pilot study, a team of researchers led by Kevin Boylan at the Mayo Clinic in Jacksonville, Fla., found that PNF-H levels in plasma measured over a period of four months were significantly increased in people with ALS compared to similarly aged healthy (control) individuals.

Now the same researchers have built on the results of their initial study, demonstrating:

  • an association between higher PNF-H levels in spinal fluid and faster rate of decline at both four months and 12 months of follow-up; and
  • an association between higher blood PNF-H levels and shorter survival time.

The researchers noted that average blood levels of PNF-H were two to three times higher in people with ALS who had bulbar onset than in those whose ALS symptoms started in the limbs. This raises the possibility that higher PNF-H levels in blood may reflect the effects of bulbar involvement — which has been shown in other studies to correlate with shorter survival time.  

The researchers say their findings support continued study of PNF-H as a potential biological indicator, or biomarker, of disease progression in ALS. This in turn could help speed drug development for ALS.

"If there were a way to identify people who are likely to have relatively faster progression, it should be possible to conduct therapeutic trials with smaller numbers of patients in less time than is required presently," Boylan said in a Nov. 19 press release.

The study team published its findings online Oct. 31, 2012, in the Journal of Neurology, Neurosurgery & Psychiatry. See: Phosphorylated Neurofilament Heavy Subunit (pNF-H) in Peripheral Blood and CSF as a Potential Prognostic Biomarker in Amyotrophic Lateral Sclerosis (access to the full paper requires a subscription or a one-time fee).

‘Disease in a dish’ at Emory Laboratory

Emory University School of Medicine in Atlanta has established the Laboratory of Translational Cell Biology (LTCB), dedicated to the creation and use of induced pluripotent stem cells (iPSCs) for translational research and drug screening in neurological disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease and spinal muscular atrophy (SMA).

The iPSCs are cells taken from mature organs (for example, the skin, stomach, liver or brain) and then converted back to pluripotent stem cells (an earlier stage of development), after which they can be coaxed along specific developmental lines in the laboratory. Their generation does not involve the destruction or manipulation of human embryos.

ALS disease models made from iPSCs feature DNA (akin to a "genetic blueprint") taken from people with the disease. This allows scientists to study ALS-causing flaws and mechanisms in human cells that reflect the genetic background in which the disease naturally occurs. In addition, such human stem cell research models are expected to eliminate some of the difficulties associated with using mice and other research animals as models of human disease.

The nature of iPSC-derived models also makes it possible to test experimental therapies on a patient's own cells as a means of determining the best possible treatment for each individual.

Gary Bassell, professor of cell biology and neurology at Emory, is the scientific director at LTCB. Wilfried Rossoll, assistant professor of cell biology, has been named associate director. (Rossoll has an MDA grant to study the effects of toxic TDP43 protein on nerve cells in ALS.)

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