Role of Ssdp in Neurodevelopment and Autism-like Behaviors

Abstract

1p32.3 microdeletion/duplication is implicated in many neurodevelopmental disorders-like phenotypes such as developmental delay, intellectual disability, autism, macro/microcephaly, and dysmorphic features. The 1p32.3 chromosomal region harbors several genes critical for development, however, their validation and characterization remain inadequate. One such gene is the single-stranded DNA binding protein 3 (SSBP3) and its Drosophila melanogaster ortholog, called sequence-specific single-stranded DNAbinding protein (Ssdp), was studied for its role in autism-associated phenotypes, using overexpression and knockdown models. Ssdp overexpression caused morphological alterations in Drosophila wing, mechanosensory bristles, and head. Ssdp manipulations also affected the neuropil brain volume and glial cell number in larvae and adult flies. We show that the canonical Wnt signaling pathway may be implicated in the neurodevelopment role of Ssdp. RNA sequencing revealed perturbation of oxidative stress-related pathways in heads of Ssdp overexpressing flies. Furthermore, Ssdp overexpressing brains showed enhanced reactive oxygen species, altered neuronal mitochondrial morphology, and dysregulated fission/fusion genes. Flies with elevated levels of Ssdp exhibited heightened anxiety-like behavior, altered decisiveness, defective sensory perception and habituation, abnormal social interaction, and feeding defects, which were phenocopied in the panneuronal Ssdp knockdown flies, suggesting that Ssdp is dosage-sensitive. Partial rescue of behavioral defects was observed upon normalization of Ssdp levels. Notably, Ssdp knockdown exclusively in adult flies did not produce behavioral and functional defects. Finally, we show that optogenetic manipulation of Ssdp-expressing neurons altered autismassociated behaviors. Collectively, our findings provide evidence that Ssdp is a critical dosage-sensitive gene in the 1p32.3 chromosomal region and is associated with ASD-like phenotypes in Drosophila.

Date of Award	2023
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences