Protein biomarker signature in patients with spinal and bulbar muscular atrophy
Andrew T.N. Tebbenkamp, Spencer B. Huggett, Vittoria Lombardi, Luca Zampedri, Abdullah AlQahtani, Angela Kokkinis, Andrea Malaspina, Carlo Rinaldi, Christopher Grunseich, Pietro Fratta, Vissia Viglietta
Andrew T.N. Tebbenkamp, Spencer B. Huggett, Vittoria Lombardi, Luca Zampedri, Abdullah AlQahtani, Angela Kokkinis, Andrea Malaspina, Carlo Rinaldi, Christopher Grunseich, Pietro Fratta, Vissia Viglietta
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Research Article Muscle biology Neuroscience

Protein biomarker signature in patients with spinal and bulbar muscular atrophy

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a slowly progressing disease with limited sensitive biomarkers that support clinical research. We analyzed plasma and serum samples from patients with SBMA and matched healthy controls in multiple cohorts, identifying 40 highly reproducible SBMA-associated proteins out of nearly 3,000 measured. These proteins were robustly enriched in gene sets of skeletal muscle expression and processes related to mitochondria and calcium signaling. Many proteins outperformed currently used clinical laboratory tests (e.g., creatine kinase [CK]) in distinguishing patients from controls and in their correlations with clinical and functional traits in patients. Two of the 40 proteins, Ectodysplasin A2 receptor (EDA2R) and Repulsive guidance molecule A (RGMA), were found to be associated with decreased survival and body weight in a mouse model of SBMA. In summary, we identified what we believe to be a robust and novel set of fluid protein biomarkers in SBMA that are linked with relevant disease features in patients and in a mouse model of disease. Changes in these SBMA-associated proteins could be used as an early predictor of treatment effects in clinical trials.

Authors

Andrew T.N. Tebbenkamp, Spencer B. Huggett, Vittoria Lombardi, Luca Zampedri, Abdullah AlQahtani, Angela Kokkinis, Andrea Malaspina, Carlo Rinaldi, Christopher Grunseich, Pietro Fratta, Vissia Viglietta

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Figure 5

Phenotypes and protein signature in AR113Q mice.

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Phenotypes and protein signature in AR113Q mice. (A) Weekly body weight ...
(A) Weekly body weight of WT and AR113Q mice from 5–30 weeks of age (2-way ANOVA). At study start, n = 47 for WT and n = 45 for AR113Q, with the number of mice that died each week during the study subtracted. (B) Kaplan-Meier survival plot comparing WT and AR113Q mice. The significance was measured at 30 weeks (Mantel-Cox). (C) Relationship between body weight and survival, categorized by AR113Q mice that died or survived. (D) Volcano plot of 92 proteins, as described previously. The red dashed line represents a P < 0.05 from multilevel metaregression models. (E and F) Volcano plots showing the correlation of protein levels with body weight or rate of death, respectively, across time in AR113Q mice. Eda2r: hazard ratio = 2.63, P = 0.003; Rgma: hazard ratio = 0.019, P = 0.0185 via time-varying Cox proportional hazard ratio models. All proteins below the red dashed line (P < 0.05) were not associated with weight or survival. The β represents the regression coefficient/slope of the model. (G) Differential abundance (log2 fold change) of Eda2r and Rgma between AR113Q and WT at different ages. n = 12 for WT and n = 15–30 for AR113Q mice, depending on each week. Week 18 samples were not available for analysis. ****P < 0.0001. (H) Change in levels of Eda2r and Rgma and association with body weight in AR113Q mice. (I) Change in levels of Eda2r and Rgma over time in AR113Q mice that died.