Pitt Pediatrics congratulates Tyler Fortuna and the Pandey Lab team for their publication in Acta Neuropathologica titled “SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration”.
GEMIN5 is essential for core assembly of small nuclear Ribonucleoproteins (snRNPs), the building blocks of spliceosome formation. Loss-of-function mutations in GEMIN5 lead to neurodevelopmental syndrome along with other patients presenting with developmental delay, motor dysfunction, and cerebellar atrophy by perturbing SMN (survival motor neuron) complex protein expression and assembly.
Currently, molecular determinants of GEMIN5-mediaied disease have yet to be explored. In their research, Fortuna and the lab identified SMN as a genetic suppressor of GEMIN5-mediated neurodegeneration in vivo. They found that an increase of SMN expression by either SMN gene therapy replacement or the antisense oligonucleotide (ASO) Nusinersen, significantly upregulated the endogenous levels of GAMIN5 in mammalian cells and mutant GEMIN5-derived iPSC (induced pluripotent stem cell) neurons.
They also found a strong functional association between the expression patterns of SMN and GEMIN5 in patient Spinal Muscular Atrophy (SMA)-derived motor neurons harboring loss-of-function mutations in the SMN gene. SMN binds to the C-terminus of GEMIN5 and requires the Tudor domain for GEMIN5 binding and expression regulation. Finally, they learned that SMN upregulation ameliorates defective snRNP biogenesis and alternative splicing defects caused by loss of GEMIN5 in iPSC neurons and in vivo. Collectively, these studies indicate that SMN acts as a regulator of GEMIN5 expression and neuropathologies.
For more studies from the Pandey Lab, follow us on Twitter and Instagram.