Seminer: Unraveling the connection between SPN1-related muscular dystrophy, SMN instability, and autophagy dysfunction – Dr. Marvan Nashabat
11 Eylül 2025 günü saat 11:00’de Dr. Marvan Nashabat “Unraveling the connection between SPN1-related muscular dystrophy, SMN instability, and autophagy dysfunction” başlıklı bir seminer verecektir.
Dr. Nashabat, Koç Üniversitesi Hücresel ve Moleküler Tıp programında doktorasını tamamlamıştır. Doktora araştırması, çekinik SNUPN patojenik varyantlarının neden olduğu yeni bir kas distrofisinin klinik ve işlevsel karakterizasyonuna odaklanmaktadır. Bu çalışma, kısa zaman önce Nature Communications dergisinde yayınlanmıştır.
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Seminer Özeti (İngilizce)
Snurportin-1 (SPN1)-related muscular dystrophy (MD), also known as limb-girdle muscular dystrophy type R29, is a recently recessive disorder characterized by progressive muscle weakness and neurological manifestations. SPN1 directs the import complex, including UsnRNPs and the SMN complex, to nuclear Cajal bodies. We previously demonstrated that SPN1 deficiency disrupts spliceosomal machinery, leading to muscular fiber defects. Given that SMN defects are associated with spinal muscular atrophy (SMA) and contribute to muscular degeneration, mitochondrial dysfunction, and autophagy impairment, we investigated the direct impact of SPN1 deficiency on SMN stability and autophagy regulation.
We demonstrated that SPN1 deficiency significantly reduced SMN protein levels and altered its localization. Transcriptomics analyses revealed alternative splicing defects and dysregulation of key autophagy-related genes. Impaired autophagic flux was confirmed by dysregulated P62 and LC3II protein levels across all SPN1 mutant models. Treatment with chloroquine and autophagy activation via rapamycin further validated this impairment. Furthermore, mitochondrial markers indicated that SPN1 is essential for proper mitochondrial clearance suggesting a critical role in mitophagy.
In conclusion,SPN1 deficiency appears to destabilize SMN protein and disrupt autophagic flux, revealing a previously unrecognized functional overlap between SPN1-related-MD and SMA pathology. These findings highlight potential therapeutic targets aimed at restoring SMN stability and autophagy homeostasis.