GEMIN5 and SMN Interaction: Clue to Potential Therapeutic Targets in GEMIN5 Related Neurodevelopmental Disorder
Deepa Rajan1, Tyler Fortuna2, Sukhleen Kour2, Anuradha Venkatakrishnan3, Anixa Muiños-Bühl4, Eric Anderson2, Krrithvi Dharini Ganesh2, Charlie Nelson2, Carolyn Ward2, Casey O'Brien2, Dhivyaa Rajasundaram2, Brunhilde Wirth4, Amit Singh3, Udai Pandey1
1Pediatrics, UPMC Childrens Hospital of Pittsburgh, University of Pittsburgh, 2University of Pittsburgh, 3University of Dayton, 4Institute of Human Genetics, Univ. of Cologne
Objective:
To identify therapeutic strategies to ameliorate symptoms caused by biallelic pathogenic variants in GEMIN5.
Background:
The survival of motor neuron (SMN) complex which is crucial for the assembly of small nuclear Ribonucleoproteins (snRNPs), is composed of several proteins including SMN protein, Gemins 2-8 and the Unr-interacting protein. While Spinal Muscular Atrophy (SMA) has been extensively studied with currently multiple therapeutic agents being available, other human diseases associate with this complex are only recently being described. We follow a large cohort of patients with biallelic mutations in GEMIN5 and associated developmental delay, motor dysfunction, and cerebellar atrophy. There are no current therapies available to modify disease in these patients.
Design/Methods:
We conducted a genetic screen and identified SMN as a genetic suppressor of GEMIN5-mediated neurotoxicity in vivo. We then upregulated SMN expression by antisense oligonucleotide treatment or by SMN cDNA expression and assessed its effect on GEMIN5 expression by Western blot analysis.
Results:
Upregulating SMN expression, either genetically or with antisense oligonucleotide (ASO) Nusinsersen, significantly increased the expression of GEMIN5 in mammalian cells and mutant GEMIN5 derived iPSC neurons. This prompted us to also investigate the levels of GEMIN5 in SMA iPSC-derived motor neurons. We found that gemin5 was significantly reduced in motor neurons derived from SMA patients with loss-of-function mutations in SMN. Moreover, GEMIN5 exhibited a strong positive correlation with the expression levels of SMN in type 1 and type 2 SMA motor neurons.
Conclusions:
Recent studies in animals and human patients have suggested a strong association between cerebellar degeneration and adult SMA mice and patients, adding further support to the connection between these two proteins. Our results provide the first evidence that SMN modifies GEMIN5-mediated neuropathology and that SMN upregulating therapies could be an effective therapeutic strategy for restoring the SMN complex defects exhibited by mutant GEMIN5 variants.