In a paper published in the Journal of Clinical Investigation, researchers from Harvard University show that survival motor neuron (SMN) proteins are degraded via autophagy, and suggest inhibiting the autophagy receptor sequestosome 1 (SQSTM1; p62) could increase SMN protein levels and help treat spinal muscular atrophy.
Previous studies suggested that SMN proteins were degraded primarily via the ubiquitin-proteasome system, but the role of autophagy in the protein's degradation -- known to degrade aggregated proteins in neurodegenerative diseases -- was unknown.
The researchers showed that starvation-induced autophagy decreased SMN protein levels compared with no starvation in human fibroblasts and embryonic kidney cells.
In motor neurons derived from healthy mice, a mouse model of SMA, and SMA patients, the researchers found that shRNA targeting SQSTM1 increased SMN levels compared with non-targeting shRNA, suggesting the receptor regulates autophagy degradation of the protein.
In the SMA mouse model, SQSTM1 knockdown increased muscle fiber size, nerve supply in muscles, the number of motor neurons in the spine, body weight and life span compared with normal SQSTM1 expression.