GABA-Related Peptides May Be Markers, Therapeutic Targets for Stiff-Person Syndrome

Paula Moyer, MA

October 07, 2004

Oct. 7, 2004 (Toronto) — Patients with stiff-person syndrome (SPS) have reduced levels of peptides related to gamma-aminobutyric acid (GABA), according to investigators from the National Institutes of Health (NIH), whose findings were presented here at the 129th annual meeting of the American Neurological Association.

Therefore, the expression of GABA-related peptides (GABARAP) may be a biomarker for the presence and severity of SPS, an immunologic disorder that has been difficult to characterize and to treat. Further, GABARAP may serve as a therapeutic target, said principal investigator Goran Rakocevic, MD, in a presentation.

The study by Dr. Rakocevic and coinvestigators showed that GABARAP and GABARAPL2 are both reduced in SPS. "This finding is consistent with the disease's characteristic impaired synaptic GABAergic function," Dr. Rakocevic said. He is a clinical fellow in the Neuromuscular Diseases Section of the Division of Intramural Research at the NIH in Bethesda, Maryland.

SPS is associated with both high-titer anti-glutamic acid decarboxylase (GAD) antibodies and impaired GABAergic neurotransmission. However, the role of GAD as the responsible autoantigen is unclear, because anti-GAD antibodies are found in diverse illnesses, such as diabetes and epilepsy. Therefore, the investigators wanted to determine whether GABARAP was more specific to SPS.

To identify signature proteomic patterns or antigens unique to SPS, they used protein chips and a mass spectometry technique known as surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) profiling. SELDI-TOF can be used to examine protein expression profiles and therefore identify antibodies unique to certain autoimmune diseases.

The investigators recruited 30 patients with SPS and 30 control subjects, and they conducted SELDI-TOF mass spectrometry on the participants' serum. They then compared the average intensities of peaks of certain proteins. When the investigators conducted a univariate analysis, they were able to distinguish SPS patients from control subjects by the expression patterns of seven protein peaks out of the 290 detected ( P < .05).

Of these, four peaks were fragments of larger proteins. These peaks were measured at 2622.9, 2746.7, 3073.9, and 3298.9 Daltons (Da), respectively. Of the four, two peaks were consistent with GABARAP and GABARAPL2, at 13,835 Da and 13,717 Da, respectively. These proteins were each significantly reduced in SPS.

However, GABARAP may have more potential than GABARAPL2 as a candidate autoantigen for treating SPS, Dr. Rakocevic said. He based this reasoning on GABARAP's interaction with gephyrin, a protein associated with inhibitory neurotransmitter receptors. Therefore, it may have more therapeutic significance than GABARAPL2, he said.

ANA 129th Annual Meeting: Abstract PL6. Presented Oct. 5, 2004.

Reviewed by Gary D. Vogin, MD

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