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bioRxiv · 10.64898/2025.11.30.691381

Interplay of Spoonbill, Larp7 and survival motor neuron, in Drosophila model of Spinocerebellar Ataxia 8 non-coding RNA associated neurodegeneration

Das, R.·Pandey, P.·Tripathi, B. K.·Maurya, B.·Mukherjee, A.·Mutsuddi, M.
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Abstract

A deeper understanding of neurodegenerative disorders at the level of genetic or environmental risk factors as well as contributing genes, pathways, and networks suggests the presence of shared molecular mechanisms. Previously, we have reported that the KH domain of the Spoonbill protein alone can suppress non-coding Spinocerebellar Ataxia 8 (SCA8) associated neurodegeneration. In the current study, we have identified dLarp7 as a novel interacting partner of Spoonbill in Drosophila. Mammalian Larp7 is associated with a neurodevelopmental disorder, Alazami Syndrome (AS). In this study, we report that dLarp7 protein is recruited into the pathogenic SCA8 RNA foci, which leads to depletion of its downstream target, 7SKsnRNA. Soaking away of Larp7 into toxic RNA foci results in its depletion from the physiological pool resulting in destabilization and depletion of 7SKsnRNP. Hence, increasing the dose of dLarp7 suppressed SCA8 associated neurodegeneration, by restoring the physiological levels of dLarp7 and 7SKsnRNP. In addition, it was observed that dLarp7 interacts with the somatic motor neuron (SMN) protein which is associated with spinal muscular atrophy (SMA). This observation led us to explore the interaction of Drosophila SMN1 orthologue with pathogenic SCA8 associated neurodegeneration. Intriguingly, SMN protein modulated molecular neuropathogenesis associated with SCA8. The presence of orthologues of Drosophila RNA binding proteins, dLarp7 and SMN, with mammalian counterparts underlines the translational importance of our findings. Our study also hints at the shared molecular mechanisms that underlies multiple neurodegenerative diseases. A novel association of Drosophila homologs of AS-linked Larp7 and SMA-causing SMN1 with SCA8 associated neurodegeneration suggests an overlap of molecular threads underlying the pathogenesis of neurodegenerative disorders.

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Das, R., Pandey, P., Tripathi, B. K., Maurya, B., Mukherjee, A., Mutsuddi, M.. 2025-12-02. Interplay of Spoonbill, Larp7 and survival motor neuron, in Drosophila model of Spinocerebellar Ataxia 8 non-coding RNA associated neurodegeneration. https://doi.org/10.64898/2025.11.30.691381

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