Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway

Prolactin: A versatile regulator of inflammation and autoimmune pathology

“…PRL-deficient mice give rise to a reduced number of hippocampal neurospheres in vitro [99] and PRL injection in chronically stressed mice sustains neurogenesis in the hippocampal dentate gyrus [100]. PRL administration increases survival in a model of severe spinal muscular atrophy, a neurodegenerative disease characterized by the loss of motor neurons [101]. Last, PRLR-deficient mice display retinal photoresponsive dysfunction and reactive gliosis, while hyperprolactinemia counteracts retinal degeneration associated with light damage [102].…”

Advances in Therapeutic Development for Spinal Muscular Atrophy

“…Prolactin, a polypeptide hormone and an activator of the JAK2/STAT5 signaling pathway, increased SMN2 transcription and SMN in both human neuron-committed teratocarcinoma (NT2) cells and the Δ7 SMA mouse model and improved the disease phenotype of Δ7 SMA mice [119]. Inhibition of the MEK/ERK pathway coupled with the activation of the AKT/CREB pathway is another mechanism recently shown to enhance SMN2 transcription (Figure 5) [118,120].…”

Of SMN in mice and men: a therapeutic opportunity

“…Finally, a modifying impact of SMN2 dosage on disease phenotype in SMA human populations has been repeatedly demonstrated, with infants with SMA type I much more likely to have two or fewer SMN2 copies as compared to those with milder phenotypes (22,23). In this issue of the JCI, two independent groups of researchers address critical issues that continue to provide uncertainty as we try to translate observations from mouse models to the clinic: in particular, these include the relevance of certain recent observations in severe mouse models, such as cardiomyopathy, and the degree to which already symptomatic patients, particularly those with SMA type I, are likely to benefit from SNM2 targeting (24,25).…”

“…In this issue, Farooq and colleagues demonstrate that the delivery of a novel therapy, prolactin (PRL), increases SMN expression in both mouse models of SMA and human cell lines via a transcriptional mechanism (24). In aggregate, their in vitro data indicate that the effect of PRL on SMN is almost certainly via the STAT5 pathway.…”

“…Prolactin is a small polypeptide protein that binds to PRL receptors triggering the JAK2/STAT5 signaling pathway. In the animal model of severe SMA, the ability of subcutaneously delivered PRL to upregulate SMN in brain and spinal cord resulted in a marked improvement in motor function, but only a modest improvement in survival (24). What makes this story potentially more compelling than that of other candidates with similar capacity for SMN upregulation is that this effect may prove more robust in humans than in mice because of the presence of a higher number of STAT5-binding sites in the human SMN2 promoter.…”