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<p>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 <i>SPAST</i> gene, a frequent cause of hereditary spastic paraplegia (SPG4) with dementia. This deletion generates fusion transcripts between <i>SPAST</i> and the downstream gene <i>SLC30A6</i>, resulting in reduced expression of ZnT6, the Golgi-resident zinc transporter encoded by <i>SLC30A6</i>. In SPAST<sup>Δe17</sup> 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 <i>SLC30A6</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Youngsun Lee,
  • Onju Ham,
  • Hana Lee,
  • Dae-Soo Kim,
  • Jung Hwa Lim,
  • Cho-Rok Jung,
  • Jae-Won Huh,
  • Mi-Young Son,
  • Mi-Ok Lee

摘要

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 SPASTΔe17 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.