JAK1/2 inhibitor ruxolitinib reduces aggregates in cardiac proteinopathy

Misfolded proteins cause or contribute to a wide range of progressive diseases that are difficult to treat. Desmin-related (cardio-)myopathy (DRM), a well-studied proteinopathy, presents with progressive muscle weakness and shortened life span. Most DRM patients display intracellular accumulation of desmin and its chaperone αB-crystallin (CRYAB). Using an unbiased high-throughput screen, we found that Janus kinase 1 (JAK1) knockdown resulted in lower CRYAB^R120G aggregates in cardiomyocytes. Here, we tested whether the JAK1/2 inhibitor ruxolitinib ameliorates the disease phenotype in CRYAB^R120G DRM models. Ruxolitinib cleared pre-existing CRYAB^R120G aggregates in neonatal rat cardiomyocytes and human induced-pluripotent stem cell-derived cardiomyocytes, and enhanced ubiquitin-proteasome system (UPS)-mediated degradation. Blocking UPS function and specifically knockdown of the E3 ligase ASB2 blunted the effect of ruxolitinib on CRYAB^R120G accumulation. In DRM mice, phospho-STAT3 and JAK1 levels were higher than in non-transgenic mice, indicating pathologically active JAK-STAT signaling. Ruxolitinib treatment resulted in lower CRYAB^R120G aggregate load and prevented cardiac dysfunction in DRM mice. Similar findings were obtained by crossing DRM mice with the cardiomyocyte-specific Jak1 knockout, suggesting JAK1 as a therapeutic target in proteinopathy.