Source: Am J Med Genet  |  Posted 7 years ago

By Paula Moyer

TORONTO, ON -- October 6, 2004 -- Reduced levels of peptides related to gamma-aminobutyric acid (GABA) may serve as markers for the presence and severity of stiff-person syndrome, and may therefore be appropriate autoantigens to consider for treatment, researchers reported here on October 5[^]th[] at the American Neurological Association 129[^]th[] Annual Meeting.

According to the investigators, GABA-related peptides and GABA(A) receptor-associated protein-like 2. are both reduced in stiff-person syndrome (SPS). This finding is consistent with the disease's characteristic impaired synaptic GABA-ergic function, said principal investigator Goran Rakocevic, MD, Clinical Fellow, Neuromuscular Diseases Section, Division of Intramural Research, National Institutes of Health, Bethesda, Maryland.

"Because [GABA-related peptides] is membrane-associated, it should be considered as a potential candidate autoantigen in this condition," he reported in his presentation.

To determine the role of GABA-related peptides in SPS, an immune-mediated neurological disorder associated with both high-titer anti-glutamic acid decarboxylase antibodies and impaired GABAergic neurotransmission. However, the role of glutamic acid decarboxylase as the responsible autoantigen is unclear, because its antibodies are found in diverse illnesses, such as diabetes and epilepsy.

Therefore, to identify signature proteomic patterns or antigens unique to SPS, the researchers used protein chips and a mass spectometry technique known as surface-enhanced[^{] [}]laser desorption/ionization time-of-flight profiling on serum samples from 30 patients with SPS and 30 healthy controls.

After baseline subtraction, Dr. Rakocevic and his investigative team compared the mean intensities of labeled protein peaks. They then conducted univariate analyses to distinguish SPS from controls by the expression patterns of seven protein peaks out of 290 detected (P <.05).

Four peaks were fragments of larger proteins and were measured at 2,622.9, 2746.7, 3073.9, and 3298.9 Daltons (Da), respectively. Two of these peaks were consistent with GABA-related peptide and GABA-related peptide L2, at 13,835 Da and 13,717 Da, respectively. These proteins were significantly reduced in SPS patients.

Dr. Rakocevic said GABA-related peptide may have more potential as a candidate autoantigen for treating SPS. He based this reasoning on its interaction with gephyrin, a protein associated with inhibitory neurotransmitter receptors, and with insertion of the GABA(A) receptor into plasma membrane. GABA-related peptide L2 interacts primarily with microtubules on the GABA(A) receptor and may therefore have less therapeutic signficance.

[Presentation title: "Proteomic Studies in Stiff-Person Syndrome (SPS): Identification of GABA-Related Peptides as Putative Biomarkers or Target Antigens." Abstract 6]