Fig 8.

Model for the selective vulnerability of motor neurons in SMA. Under normal conditions, the SMN2 gene produces smaller amounts of full-length SMN mRNA and protein in motor neurons (MN) than in non-motor neurons (non-MN) due to more inefficient exon 7 splicing. Upon loss of the protective SMN1 allele, the downstream effects of SMN deficiency in SMA MNs are exacerbated compared to non-MNs due to the lower SMN levels. These include downregulation of nuclear snRNP levels and upregulation of Cdkn1a mRNA expression. Moreover, reduced snRNP levels trigger a negative feedback loop affecting exon 7 splicing that might contribute to further decreasing SMN expression and enhancing downstream defects specifically in SMA MNs.