Abstract Details

Title GEMIN5 and SMN Interaction: Clue to Potential Therapeutic Targets in GEMIN5 Related Neurodevelopmental Disorder

Topic Child Neurology and Developmental Neurology

Presentation(s) P7 - Poster Session 7 (11:45 AM-12:45 PM)

Poster/Presentation
Number 8-001

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.

Authors/Disclosures
Deepa S. Rajan, MD, FAAN (Childrens Hospital of Pittsburgh) PRESENTER	Dr. Rajan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Dr. Rajan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Rajan has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Medlink Neurology. The institution of Dr. Rajan has received research support from National Scleroderma Foundation. The institution of Dr. Rajan has received research support from Denali Therapeutics. The institution of Dr. Rajan has received research support from Ultragenyx . The institution of Dr. Rajan has received research support from Regenxbio. The institution of Dr. Rajan has received research support from Takeda. The institution of Dr. Rajan has received research support from Prevail Therapeutics. The institution of Dr. Rajan has received research support from Children's Neuroscience Institute. Dr. Rajan has received intellectual property interests from a discovery or technology relating to health care.
Tyler Fortuna (University of Pittsburgh)	No disclosure on file
Sukhleen Kour (University of Pittsburgh Medical center)	No disclosure on file
Anuradha Chimata (University of Dayton)	No disclosure on file
Anixa Muiños-Bühl	No disclosure on file
Eric Anderson	No disclosure on file
Krrithvi Dharini Ganesh, MBBS (Tgen)	Dr. Ganesh has nothing to disclose.
Charles Nelson (UPMC Children's Hospital of Pittsburgh, Rangos Research Building)	No disclosure on file
Caroline Ward	No disclosure on file
Casey O'Brien	No disclosure on file
Dhivyaa Rajasundaram (University of Pittsburgh)	Dhivyaa Rajasundaram has nothing to disclose.
Brunhilde Wirth, PhD (Institute of Human Genetics, Univ. of Cologne)	The institution of Prof. Wirth has received research support from Deutsche Forschungsgemeinschaft. The institution of Prof. Wirth has received research support from European Commission.
Amit Singh (University of Dayton)	No disclosure on file
Udai Pandey	No disclosure on file

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