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Functional loss of  SMN1  causes proximal spinal muscular atrophy (SMA), the most common genetic condition accounting for infant lethality. Hence, the hypomorphic copy gene  SMN2  is the only resource of functional SMN protein in SMA patients and influences SMA severity in a dose-dependent manner. Consequently, current therapeutic approaches focus on  SMN2 . Histone deacetylase inhibitors (HDACi), such as the short chain fatty acid VPA (valproic acid), ameliorate the SMA phenotype by activating the  SMN2  expression. By analyzing blood  SMN2  expression in 16 VPA-treated SMA patients, about one-third of individuals were identified as positive responders presenting increased  SMN2  transcript levels. In 66% of enrolled patients, a concordant response was detected in the respective fibroblasts. Most importantly, by taking the detour of reprograming SMA patients' fibroblasts, we showed that the VPA response was maintained even in GABAergic neurons derived from induced pluripotent stem cells (iPS) cells. Differential expression microarray analysis revealed a complete lack of response to VPA in non-responders, which was associated with an increased expression of the fatty acid translocase CD36. The pivotal role of CD36 as the cause of non-responsiveness was proven in various  in vitro  approaches. Most importantly, knockdown of CD36 in SMA fibroblasts converted non- into pos-responders. In summary, the concordant response from blood to the central nervous system (CNS) to VPA may allow selection of pos-responders prior to therapy. Increased CD36 expression accounts for VPA non-responsiveness. These findings may be essential not only for SMA but also for other diseases such as epilepsy or migraine frequently treated with VPA.

VPA response in SMA is suppressed by the fatty acid translocase CD36