No abstract

Neurodegenerative diseases are characterized by a loss of neurons that leads to cognitive and behavioral dysfunction. Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting millions of people in the United States and worldwide, followed by Parkinson's disease (PD). While some early onset forms of AD and PD are hereditary, the sporadic or late-onset cases are believed to result from lifestyle and environmental factors. On the contrary, Huntington's disease (HD) is a neurodegenerative disease solely caused by mutations in the gene for huntingtin protein. The disease mechanisms at play for all three disorders remain elusive, hampering efforts to develop effective therapeutic interventions. In light of this, the discovery of robust biomarkers is crucial in order to identify people at risk for AD and PD, preferably before symptoms arise. For all three diseases, the identification of biomarkers would not only allow development of treatments but also evaluation and adjustment of these with disease progression. It is now understood that neuroinflammation plays a crucial role in neurodegenerative diseases, along with subsequent immune activation. Therefore, research is actively ongoing to discover and evaluate inflammatory and immune-related biomarkers. Recent progress in this area for AD, PD, and HD is presented here.

On-bead screening of one-bead-one-compound (OBOC) libraries is a useful procedure for the identification of protein ligands. An important aspect of this experiment is the method by which beads that bind the target protein are separated from those that do not. Ideally, such a method would be rapid and convenient and result in the isolation of 100% of the "hits" with no false positives (beads that display compounds that are not good ligands for the target). We introduced a technique in which beads that have bound a labeled target protein can be magnetized, thus allowing their convenient isolation ( Astle et al. Chem. Biol. 2010 , 17 , 38 - 45 ). However, recent work in our laboratory and others has shown that magnetic hit recovery can result in the isolation of large numbers of false positives and has also suggested that many true hit beads are missed. In this study, we employ a well-defined model system to examine the efficiency of various magnetic hit isolation protocols. We show that the choice of reagents and the particular operations employed are critical for optimal results.

Summary A major goal in understanding autoimmune diseases is to define the antigens that elicit a self-destructive immune response, but this is a difficult endeavor. In an effort to discover autoantigens associated with type 1 diabetes (T1D), we used epitope surrogate technology that screens combinatorial libraries of synthetic molecules for compounds that could recognize disease-linked autoantibodies and enrich them from serum. Autoantibodies from one patient revealed a highly phosphorylated form of peripherin, a neuroendocrine filament protein, as a candidate T1D antigen. Peripherin antibodies were detected in 67% of donor patient sera. Further analysis revealed that the T1D-associated antibodies only recognized a dimeric conformation of peripherin. These data explain why peripherin was dismissed as an important T1D antigen previously. The discovery of this novel autoantigen would not have been possible using standard methods, such as hybridizing serum antibodies to recombinant protein arrays, highlighting the power of epitope surrogate technology for probing the mechanism of autoimmune diseases.

Risk of type 1 diabetes at 3 years is high for initially multiple and single Ab+ IT and multiple Ab+ NT. Genetic predisposition, age, and male sex are significant risk factors for development of Ab+ in twins.