Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, is a degenerative disease characterized by loss of motor neurons in the spinal cord, skeletal muscle atrophy, and death. SMA is caused by the disruption or deletion of the survival motor neuron (SMN) gene and a substantial reduction in the associated SMN protein; however, the specific role SMN loss plays in disease pathology is still unclear. Although motor neuron loss is essential for the development of SMA, growing evidence from our group and others suggests that astrocytes contribute to the complex SMA phenotype. In support of this, we have found that SMA astrocytes (i) exhibit a flattened morphology with short processes, (ii) lack growth factor production, (iii) have aberrant MAPK signaling, and (iv) induce motor neuron loss. Importantly, these glial cell abnormalities occur prior to overt motor neuron loss Moreover, recent data from our group show that SMA patient stem cell-derived astrocytes exhibit increased production and secretion of microRNA (miR) 146a compared with control astrocytes. This is of particular interest because miR-146a production, as well as the previously mentioned astrocyte characteristics, is linked to cellular senescence. Although senescence implies a tumor-suppressed state, it can induce pathological changes in neighboring cells due to altered proteomic profiles. In the human brain, there is accumulating evidence that senescent astrocytes contribute to the phenotype of age-related neurodegenerative diseases. Because SMA is an early-onset disease, our findings represent a novel paradigm of accelerated aging that is specifically caused by low SMN levels and is supported by preliminary data showing increased senescence associated gene and protein expression in SMA astrocytes. Importantly, we have also found that re-expression of SMN in SMA patient stem-cell derived astrocytes reverses the morphological changes, re- establishes growth factor production, minimizes aberrant MAPK activation, and returns miR-146a expression to control levels. In parallel, recent studies have found that the transcription factor GATA6 is a direct target of SMN, is upregulated in human and mouse SMA samples, and its level correlates with SMA severity. We find increased GATA6 transcript and protein expression in SMA astrocytes, and our preliminary data indicate an interaction between GATA6 and miR-146a. Therefore, we hypothesize that SMN deficiency causes astrocyte senescence by permitting the up-regulation of GATA6. This hypothesis will be tested via in vitro and in vivo approaches. We will knock-out and over-express GATA6 in SMA astrocytes, monitoring the senescent phenotype and its impact on the function and survival of co-cultured motor neurons. Additionally, we will cross GATA6 knockout mice with the widely used SMN?7 mouse model to test whether reduced GATA6 expression mitigates astrocyte malfunction and prevents motor neuron loss. These experiments offer novel insights into SMN-mediated astrocyte dysfunction and test therapeutic strategies for SMA treatment.
Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, is characterized by loss of motor neurons in the spinal cord, skeletal muscle atrophy, and death due to a reduction in survival motor neuron (SMN) expression. Astrocytes contribute to disease pathology, and we hypothesize that this is due to astrocyte senescence and aberrant GATA6 expression. The proposed experiments offer novel insights into SMN-mediated astrocyte dysfunction and test therapeutic strategies for SMA treatment.
