Alu-mediated SPAST deletion impairs golgi zinc transport and reveals a druggable vulnerability

Alu elements are primate-specific retrotransposons known to mediate structural genomic alterations associated with neurological disorders, yet their underlying disease mechanism remains incompletely understood. Here, we leveraged human pluripotent stem cell-derived cortical organoids and xenografts to model an Alu-mediated exon 17 deletion in the SPAST gene, a frequent cause of hereditary spastic paraplegia (SPG4) with dementia. This deletion generates fusion transcripts between SPAST and the downstream gene SLC30A6, resulting in reduced expression of ZnT6, the Golgi-resident zinc transporter encoded by SLC30A6. In SPAST^Δe17 organoids, we detected pronounced cytosolic zinc accumulation, Golgi fragmentation, lipid dysregulation, and increased aggregation of Aβ and ubiquitin. These phenotypes were further exacerbated in xenograft models, concomitant with ubiquitin-positive inclusions resembling those found in patients' brains. Knockdown of SLC30A6 in control organoids recapitulated the neurodegenerative features, supporting a critical role of ZnT6 in maintaining neuronal homeostasis. Intervention with TPEN, a zinc-specific chelator, or a GRASP55-blocking antibody to prevent Golgi fragmentation significantly restored Golgi integrity and reduced Aβ levels. Notably, immunohistochemistry revealed heterogeneous ZnT6 expression in AD brains; however, both ZnT6-low and ZnT6-high cases consistently exhibited elevated p-GM130, a marker of Golgi fragmentation. Finally, we detected a SPAST-SLC30A6 chimeric transcript in brain tissue from a sporadic AD patient. Together, our findings identify a primate-specific cascade linking Alu-mediated genomic rearrangements to zinc dyshomeostasis and Golgi pathology and suggest that dysregulation of the ZnT6-Golgi axis may represent a vulnerability and therapeutic target in structural variant-driven neurodegeneration and possibly in a subset of sporadic cases.