Nusinersen rescues taurine deficiency in severe Spinal Muscular Atrophy

Abstract Background Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality resulting from ubiquitous SMN deficiency, disrupts key biological processes such as neurotransmission, oxidative stress, and inflammation, all of which may be modulated by the neurotransmitter taurine. However, it remains uncertain whether a connection exists between SMN deficiency and the regulation of taurine homeostasis within the central nervous system (CNS). Methods We used high-performance liquid chromatography (HPLC) to quantify taurine in the spinal cord, brainstem, cortex, and cerebellum in SMN∆7 mice, during postnatal development. We then translate our observation into the clinic by measuring taurine concentrations in the cerebrospinal fluid (CSF) from control individuals (n = 7) and SMA patients of varying disease severity (n = 37) before and after therapy with the SMN-inducing drug Nusinersen. Results Our data show a downregulation of taurine levels in the brainstem of SMN∆7 mice at late symptomatic stage relative to control littermates. Furthermore, we highlight a taurine reduction in the CSF of naïve SMA type 1 patients compared to controls. Importantly, Nusinersen treatment restored the taurine deficit in these SMA patients. Conclusions These findings demonstrate that SMN deficiency dysregulates taurine homeostasis in the CNS of overt symptomatic mouse models and SMA patients affected by the most severe form of the disease. They also reveal the therapeutic efficacy of Nusinersen treatment in correcting this amino acid metabolism deficit. However, further research is needed to determine the mechanisms by which SMN deficiency causes taurine dysregulation and its potential contribution to SMA pathology.